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.     

The mechanism of aldosterone response to furosemide test in patients with Shy-Drager syndrome

We examined the renin-angiotensin-aldosterone system in seven patients with Shy-Drager syndrome by studying their response to the stimulation of 1 mg/kg furosemide injection followed by sitting for 1 hour. Six of the seven patients showed a low response of plasma renin activity to the stimulation. However, in five of the low responders, the plasma aldosterone levels after stimulation were observed to be similar to those of the control subjects; in addition, an increment in the plasma cortisol level appeared although no such increment was observed in normal subjects. Next, we studied the aldosterone response to angiotensin II. The five patients who showed a low plasma renin activity response and a normal aldosterone response to furosemide administration also showed low plasma aldosterone response to angiotensin II. Furthermore, in the patients who demonstrated a low plasma renin activity response and a normal aldosterone response to furosemide administration, the pretreatment with 2 mg dexamethasone for 2 days caused a marked inhibition of aldosterone response to the stimulation. These findings suggested that in most patients with Shy-Drager syndrome, the plasma aldosterone response to the stimulation of furosemide injection followed by sitting for 1 hour might be controlled by ACTH but not by plasma renin activity.     

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.     

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.     

Plasma atrial natriuretic peptide, plasma renin activity and aldosterone during treatment of hyperthyroidism due to Graves' disease

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and aldosterone were consecutively measured during methimazole treatment in patients with hyperthyroidism due to Graves' disease. ANP values of untreated hyperthyroid patients varied greatly from patient to patient, but decreased progressively with a decrease of serum thyroid hormone concentration during methimazole treatment. PRA was elevated in hyperthyroid patients but less aldosterone was secreted as evidenced by lower aldosterone/PRA ratio in these patients than in normal subjects and in hypertensive patients treated with thiazide. In addition, aldosterone/PRA ratio increased progressively with a decrease of ANP during methimazole treatment. The data indicated that ANP secretion was increased and ANP thus secreted depressed aldosterone secretion in hyperthyroid patients. Propranolol depressed pulse rate but failed to affect ANP secretion. It is suggested that thyroid hormone specifically acts on myocytes to stimulate ANP secretion but physiologic significance of such increased ANP secretion remains to be solved.     

Regulation of aldosterone secretion in primary aldosteronism.

Plasma aldosterone, plasma renin activity and plasma cortisol were determined in patients with primary aldosteronism in response to posture and at short-time intervals overnight while the patient were supine. In the 5 patients with an aldosterone-producing adenoma postural changes in plasma aldosterone were paralleled by those in cortisol while plasma renin activity was generally undetectable indicating an ACTH-dependent secretion of aldosterone. This concept was supported by the observation that in 3 of these patients who were tested overnight 1. episodic secretion of plasma aldosterone was paralleled by those of cortisol and 2. episodic secretion of plasma aldosterone could be blunted by dexamethasone. In the patient with idiopathic adrenal hyperplasia concomittant changes in plasma aldosterone and plasma renin activity occurred. The assumption that in this patient the fluctuations in plasma aldosterone were mediated through changes in renal renin secretion was supported by the finding that episodic secretion of plasma aldosterone persisted under suppression of ACTH-secretion by dexamethasone. Our results indicate, that the described procedures may all serve as diagnostic criteria to differentiate between aldosterone-producing adenoma and idiopathic adrenal hyperplasia.     

Sodium outflow rate through lymphocyte cell membranes, serum levels of sodium, potassium, aldosterone, total catecholamines, 6-keto- PGF2alpha and plasma renin activity in patients with primary arterial hypertension treated with captopril]

Sodium ions outflow rate through lymphocyte membranes, serum sodium, potassium, aldosterone, total catecholamines and 6-keto-PGE alpha levels, and plasma renin activity were studied in patients with mild hypertension associated with low and hugh plasma renin activity treated with captopril in a single dose of 12.3 mg and after the treatment with daily doses of 12.5 mg and 25 mg for 3 days. It was found, that captopril in hypertensive patients with high plasma renin activity decreases both systolic and diastolic blood pressure, decelerates heart rate, and decreases serum total catecholamines and plasma renin activity. Sodium ions outflow rate and serum sodium, potassium, aldosterone, and 6-keto-PGE alpha remain unchanged. Captopril in hypertensive patients with low plasma renin activity. The remaining parameters are unchanged. Moreover, it was noted that serum 6-keto-PGE alpha levels are lower in hypertensive patients with low plasma renin activity.     

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.     

Serum aldosterone and protein-binding variables in Yanomama Indians: a no-salt culture as compared to partially acculturated Guaymi Indians

Yanomama Indians from the jungles of southern Venezuela and northern Brazil excreted 1 +/- 1.5 mEq of Na and 203 +/- 109 mEq of K and had low blood pressure (BP), 102/62 mm Hg). In comparison, Guaymi Indians of Panama excreted 103 +/- 50 mEq of Na and 118 +/- 52 mEq of K and had significantly higher BP (114/75 mm Hg, p less than 0.001). Elucidating the renin-aldosterone axis, total upright serum aldosterone in 34 Yanomama was high (85.6 +/- 78 ng/100 ml). The binding capacities of thermolabile (ABG) and thermostable (ABG-Ts) serum globulins for aldosterone were elevated at 23.8 +/- 6 and 14.9 +/- 2.6%, respectively; consequently, total ABG- plus ABG-Ts- bound aldosterone was as high as 38.6 +/- 6.3%. Plasma renin activity (PRA 10.3 +/- 2.4 ng/ml/h) and urinary aldosterone 18-glucuronide (70.3 +/- 30 micrograms/24 h) in 17 Yanomama were also very high. In contrast, total serum corticosteroids and corticosteroid-binding globulin (CBG) binding capacity were normal, suggesting normal ACTH activity. PRA correlated positively with total (r = 0.47, p less than 0.05) and free (r = 0.47, p less than 0.05) serum aldosterone, which in turn showed a negative trend with Na (r = 0.33, NS) excretion. The effect of high dietary K appeared less important to aldosterone stimulation and PRA suppression. ABG-bound aldosterone (r = 0.43, p less than 0.01) as well as ABG-Ts (r = 0.56, p less than 0.05) were negatively correlated with diastolic but not systolic BP. The total ABG- and ABG-Ts-bound fraction correlated with diastolic BP (r = 0.43, p less than 0.05) in contrast to the free fraction (r = 0.08, NS) or total aldosterone (r = -0.09). Apparently, only bound serum aldosterone is important for the maintenance of diastolic BP. High serum aldosterone, with elevated excretion, indicates an increased secretion rate; increased serum protein binding suggests an increased tissular activity and alterations in aldosterone metabolism. In Guaymi Indians both total plasma aldosterone (14.5 +/- 65 ng/100 ml) and urinary aldosterone (8.1 +/- 4.8 micrograms/creatinine excretion) were normal. ABG-binding capacity for aldosterone was moderately elevated (17.8 +/- 4.8) and of ABG-Ts normal (10.2 +/- 1.2) suggesting a nearly normal aldosterone metabolism and regulation. The BP of Guaymi was significantly higher than that of the Yanomama.     

Need for beta-blockade in hypertension reduced with long-term minoxidil.

Sequential changes in plasma renin activity and urinary aldosterone and noradrenaline were assessed in eight patients with severe hypertension after minoxidil had been added to their treatment. Doses of 2.5--27.5 (mean 12.5) mg/day reduced the mean blood pressure from 166/113 +/-6/2 mm Hg to 124/88+/-4/2 mm Hg in one week. Plasma renin activity and urinary aldosterone and noradrenaline increased twofold to threefold initially but returned to baseline values within two to three weeks and remained unchanged during a mean follow-up of 5.1 months. Beta-blocking drugs were then withdrawn slowly in six patients without adverse effects, though blood pressure and heart rate increased in three patients, who required minimal doses of beta-blockers. Plasma renin activity and urinary aldosterone and noradrenaline did not change significantly after beta-blockade had been stopped. We conclude that the need for beta-blockade is greatly reduced with long-term minoxidil treatment and that it may be unnecessary in some patients.     

Absent aldosterone response to metoclopramide in patients with high spinal cord transection: evidence that metoclopramide stimulates aldosterone secretion through central pathways

This study evaluates dopaminergic regulation of aldosterone secretion in 6 patients with high spinal cord transections. Administration of the dopamine antagonist metoclopramide resulted in a marked rise in plasma aldosterone and 18-hydroxycorticosterone levels in 12 normal individuals, but no change in plasma levels of these zona glomerulosa corticosteroid products in spinal cord patients. Spinal cord transected patients also did not have the rise in plasma renin activity that was observed in normals following metoclopramide administration. Basal levels of aldosterone, 18 hydroxycorticosterone, corticosterone and renin activity as well as the aldosterone responses to graded dose infusion of adrenocorticotropin were similar in the spinal cord patients and the normals. These data suggest that dopaminergic regulation of adrenal zona glomerulosa corticosteroid and renal renin secretion is absent in patients with high spinal cord transections, suggesting that intact neural pathways from the central nervous system are necessary for metoclopramide stimulation of aldosterone and renin secretion in men. Since basal plasma aldosterone levels were normal in spinal cord transected patients, it appears that the absence of dopaminergic control does not result in elevated secretion.     

Plasma renin activity, active and inactive renin concentrations, and their responses to beta 1-adrenoceptor blockade with metoprolol in hyperthyroidism

Plasma renin activity (PRA), plasma renin concentration (PRC), inactive renin concentration (IRC) and total renin concentration (TRC) were measured in 31 normal controls and in 8 patients with hyperthyroidism. TRC was determined as angiotensin I generated with sheep renin substrate after an acid activation of plasma. The angiotensin I of non-acidified plasma was expressed as PRC. IRC was calculated as TRC minus PRC. The mean values for PRA, PRC, IRC and TRC were significantly (P less than 0.05 to P less than 0.01) higher in the hyperthyroid patients than in the normal or euthyroid controls. The administration of a beta 1-adrenergic blocker, metoprolol (120 mg/day for 14 days), produced a significant (P less than 0.05 to P less than 0.01) fall in levels of T4, PRA and TRC, and reduced the active renin ratio calculated from PRC/TRC significantly (P less than 0.025), as compared to the pretreatment values. Our observations support the idea that the higher PRA in hyperthyroidism is due to an increased secretion of renin. Furthermore, the results may indicate that the conversion of inactive to active renin is accelerated in hyperthyroidism, possibly by an increased sympathetic activity.     

Plasma renin activity and urinary kallikrein excretion in lead-exposed workers as related to hypertension and nephropathy

Urinary kallikrein activity and plasma renin activity (PRA) in supine and erect positions were determined in 22 men occupationally exposed to lead. In eight of them, suffering from hypertension and/or nephropathy, urinary kallikrein activity was low or absent, while PRA was normal or reduced. The other fourteen non-symptomatic workers showed normal or reduced urinary kallikrein activity and variable PRA. Urinary kallikrein activity of lead-exposed workers was significantly correlated with upright PRA.The relation between lead-exposure and essential hypertension is discussed.     

Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.     

Comparison of Surgery and Prolonged Spironolactone Therapy in Patients with Hypertension,Aldosterone Excess,and Low Plasma Renin

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery.Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment.In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied.Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped.In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.     

Adrenal sensitivity to angiotensin II and undiscovered aldosterone stimulating factors in hypertension

We have determined that the adrenal glands of patients with the syndromes of low-renin essential hypertension and idiopathic hyperaldosteronism are abnormally sensitive to the steroidogenic effect of angiotensin II. The mechanism of this heightened responsiveness to angiotensin II is unknown but may be due to the bilateral adrenal hyperplasia present in many patients with these low-renin hypertension syndromes. We have found that metoclopramide, a dopamine antagonist, causes three-fold increases in levels of plasma aldosterone in normal subjects. These increases could not be accounted for by changes in plasma renin activity, ACTH or potassium. Metoclopramide does not stimulate bovine adrenal glomerulosa cells to produce aldosterone in vitro, suggesting that it stimulates the secretion of aldosterone in vivo indirectly, by increasing the levels or the activity of an undefined aldosterone stimulating factor. We have also found that human urine, after partial purification, stimulates bovine adrenal glomerulosa cells to produce aldosterone in vitro. Urine samples from patients with low-renin essential hypertension or idiopathic hyperaldosteronism have more stimulating activity than urine samples from normal subjects. These preliminary findings support the hypothesis that excessive production of an undefined aldosterone stimulating factor may be the basic abnormality in some cases of idiopathic hyperaldosteronism and low-renin essential hypertension.     

Effect of hypoxemia on the renin-angiotensin-aldosterone system in humans

Hypoxemia was induced in five subjects older than 40 (group 1) and five younger than 35 yr (group 2) on normal and low-salt diets by having the subjects breathe hypoxic gas. The fractional inspired O2 of the hypoxic gas was regulated so that group 1 hemoglobin saturations fell to 90% for 1 h. Group 2 subjects had desaturation to 90% for 1 h followed by desaturation to 80% for a 2nd h. Plasma renin activity (PRA), angiotensin-converting enzyme activity (ACE), and plasma cortisol levels did not change during hypoxemia. Plasma aldosterone levels fell in both groups during the 1st h of hypoxemia. Decreases were greatest during salt restriction and were significant (P less than 0.01) for the combined groups. Plasma aldosterone levels plateaued during the 2nd h of more severe hypoxemia in group 2. Hepatic blood flow, measured by indocyanine green clearance, and the adrenal response to exogenous adrenocorticotropic hormone, measured by changes in plasma cortisol and aldosterone, were not changed by hypoxemia in group 2 subjects. These results indicate that plasma aldosterone falls during hypoxemia despite unchanged PRA, ACE, hepatic blood flow, and adrenal function.     

The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.

The effect of metabolic acidosis on the renin-aldosterone system remains unclear. In the present study anesthetized mongrel dogs (n = 19) were infused at similar rates with 0.45% NaCl (controls), HCl or NH4Cl (2.5mEq/kg) for 1--3 h. The induced metabolic acidosis in the two experimental groups was not associated with increases in plasma renin activity. Plasma cortisol (as a marker for ACTH secretion) and serum potassium concentration increased in both HCl- and NH4Cl-treated animals. Plasma aldosterone increased after 30 min in the HCl group and 60 min in the NH4Cl group and did not change in controls. These findings demonstrate that metabolic acidosis induced by HCl or NH4Cl is associated with increased aldosterone production without concomitant changes in plasma renin activity.     

卡托普利试验过程中颈动脉斑块与醛固酮含量相关指标变化的相关性研究

目的:研究卡托普利试验过程中血浆醛固酮(PAC)相关指标的变化与颈动脉斑块的相关性。方法:选择在本院住院进行高血压病因筛查并完成了卡托普利试验,且颈动脉彩超资料完整的83例患者为研究对象。以颈动脉彩超诊断结果为分组标准,有颈动脉斑块者为斑块组(57例),无颈动脉斑块者为无斑块组(26例),分析两组患者PAC、血浆肾素活性(PRA)、PAC与PRA的比值(ARR)等指标的变化与颈动脉斑块之间的相关性。结果:颈动脉斑块检出率为68.67%。与无斑块组比较,斑块组患者的年龄更大,载脂蛋白A1(APOA1)水平更低(P均<0.05),卡托普利试验前后斑块组患者的ARR差值更低,PAC及PRA的差值更大(P均<0.05);其中,斑块组PAC及PRA的差值为正;无斑块组此二差值为负,斑块组ARR的差值为负,无斑块组该差值为正。Logistic回归分析表明,在排除了性别等因素之后,仅年龄、卡托普利试验前后PAC差值及ARR差值为颈动脉斑块形成独立的危险因素。结论:在进行高血压病因筛查的住院高血压患者中,颈动脉斑块的检出率较高,卡托普利试验前后PAC的差值及ARR的差值为颈动脉斑块形成独立的危险因素。