THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA WITH NORMAL GLOMERULAR FILTRATION RATE: IS THERE A DEFICIENCY IN VASODILATOR PROSTAGLANDINS?

1. In Gordon's syndrome (GS; a syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate), excessive proximal sodium reabsorption leads to suppression of renin and aldosterone, hyperkalaemia and hyperchloraemic acidosis. 2. Low urinary levels of vasodilator prostaglandins (PG) have been reported in GS, suggesting renal hypoprostaglandinism as a pathophysiological mechanism. 3. In four cases of GS, levels of vasodilator prostaglandins PGE2 and 6-keto-PGF1 alpha were low. 4. In one case of GS, low PGE2 levels were normalized by dietary salt restriction or diuretic therapy.     

Study of the effects of cicletanine on the renin-angiotensin-aldosterone system

The effect of a single dose of 50 mg of cicletanine on plasma renin activity, plasma potassium and aldosterone, blood pressure, urinary volume and sodium and potassium excretion was compared to the effect of the same dose given for 9 days in eight normal volunteers in metabolic balance on 120-140 mEq of sodium and 50-70 mEq potassium. Following 4 days of this standardized diet, the normal volunteers received their first dose of cicletanine after an overnight fast and blood was collected at 30 min, 2, 4 and 6 h for plasma renin activity and aldosterone. Urine excreted following a modest water load was also collected and analysed over a 6-h period. Following the single dose there was an increase in PRA at 1 and 2 h, while there was no such increase with chronic administration. Plasma aldosterone, however, showed no difference between acute and chronic administration of cicletanine treatment. Also plasma uric acid levels increased with acute but not chronic cicletanine. There were no differences in heart rate and blood pressure responses, nor in urine volume, urinary sodium or potassium excretion, or plasma potassium between the different treatments. This study strongly suggests that the antihypertensive effect of cicletanine is not the result of an increased diuresis, as in this case enhanced urinary electrolyte excretion and increased plasma renin activity and aldosterone would be mandatory following chronic administration. Recent evidence suggests that the dissociation between plasma renin activity and aldosterone is the consequence of an effect of cicletanine on intracellular calcium mobilization. This mode of action would explain both the antihypertensive as well as the aldosterone secretion reducing effect of cicletanine.     

SODIUM AND VOLUME DYSREGULATION AFTER APPARENTLY NORMAL PREGNANCY IS SUGGESTED BY ABNORMAL LEVELS OF ATRIAL NATRIURETIC PEPTIDE, RENIN AND ALDOSTERONE

1. Plasma atrial natriuretic peptide (ANP), renin activity, aldosterone, sodium, potassium and serum total protein and albumin during and after 14 normal pregnancies were compared with age-matched controls. 2. None developed toxaemia and all delivered healthy babies. 3. During pregnancy, plasma renin activity and aldosterone were significantly (P less than 0.01) higher and potassium, total protein and albumin significantly lowew (P less than 0.01) than in controls, while ANP was not different from the control level. 4. At 6-13 weeks postpartum, a significant (P less than 0.01) suppression of renin and aldosterone was accompanied by significant (P less than 0.01) elevation of atrial natriuretic peptide when compared with controls. 5. The hormonal changes are consistent with 'effective plasma volume' reduction during pregnancy and persistent volume expansion after pregnancy, perhaps due to a renal glomerular lesion sustained late in pregnancy. In contrast, levels of potassium, total protein and albumin are consistent with haemodilution during pregnancy and its correction postpartum. 6. Measurements available in seven women 40-120 weeks postpartum showed normal renin and aldosterone levels in most, but ANP was still elevated. 7. Pregnancy may have a protracted effect on volume regulation.     

The effects of beta-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.

1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta-adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.     

THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA WITH NORMAL GFR. A UNIQUE PATHOPHYSIOLOGICAL MECHANISM FOR HYPERTENSION?

Based on 28 reported patients, constant features of the syndrome of hypertension and hyperkalaemia are hyperkalaemia, hyperchloraemia, normal renal glomerular function and, in all adult patients, hypertension. Inconstant features include short stature, intellectual impairment and muscle weakness. Levels of renin and aldosterone are low, but respond to dietary salt restriction and diuretic therapy, both of which reverse the hypertension and hyperkalaemia. The basic abnormality is excessive renal sodium retention, leading to chronic suppression of renin and aldosterone; the latter is then hyporesponsive to the hyperkalaemic stimulus. Dietary salt loading or impaired production of any natriuretic or chloriuretic factor (for example atrial natriuretic peptide or renal natriuretic prostaglandins) would predispose to development of the syndrome. With normal GFR, this appears to be a unique mechanism for hypertension and hyperkalaemia.     

Volume independent stimulation of renin secretion by a single dose of amiloride in man

The regulation of renin secretion is not understood in detail. There is evidence that amiloride (CAS 17440-83-4) has a stimulatory effect on the renin secretion but it is still in question whether this is volume and/or sodium independent. The purpose of this study was to investigate whether a single dose of amiloride has a direct stimulatory effect on the renin secretion in humans independent of its diuretic effect. Blood pressure, plasma renin activities and plasma aldosterone concentrations as well as serum electrolytes and serum creatinine were assessed in 11 healthy male humans over a period of 6 hours after a single dose of 20 mg of amiloride (Midamor), or placebo. Furthermore every hour urine was collected for analysis of urinary creatinine and electrolytes. To avoid a possible effect on the renin secretion via augmented diuresis induced by amiloride the urinary volume loss was replaced by 0.9% NaCl solution. There was a decrease in plasma renin activities and plasma aldosterone concentrations after amiloride and placebo administration, but the plasma renin activity after amiloride was significantly higher compared with placebo. Also the plasma aldosterone concentration was higher after amiloride compared with placebo, but the difference did not reach statistical significance. Serum and urinary concentrations of sodium and potassium clearly confirmed the known potassium-saving and natriuretic effect of amiloride. Serum creatinine concentrations decreased and urinary sodium chloride concentrations increased due to the administered volume load using physiologic sodium chloride solution. The present study provides evidence that amiloride induces renin secretion by direct mechanisms in man, which might go along with augmented aldosterone secretion.     

LEVELS OF ATRIAL NATRIURETIC PEPTIDE ARE NOT ALWAYS CONSISTENT WITH ATRIAL PRESSURE: IS THERE ALTERNATIVE REGULATION AS EVIDENCED IN GORDON'S AND BARTTER'S SYNDROMES?

1. In Bartter's syndrome, atrial pressures were low, consistent with volume contraction, while atrial natriuretic peptide (ANP) levels were unexpectedly elevated. Infusion of normal saline increased both right atrial pressure (RAP) and ANP levels, while administration of prostaglandin inhibitors raised RAP, probably due to volume expansion, but ANP levels fell paradoxically. 2. In Gordon's syndrome, atrial pressures were unexpectedly low or normal despite volume expansion, while ANP levels were normal. Pressor infusions of angiotensin II either raised right and left atrial pressures (LAP) without increasing ANP, or increased ANP without increasing atrial pressures. 3. In these two syndromes, atrial pressures and ANP levels were poorly correlated, leading to the proposal that other regulators of ANP may be important.     

PLASMA ALDOSTERONE LEVELS AFTER KCI LOADING IN RATS ADAPTED TO A HIGH POTASSIUM DIET

Plasma levels of aldosterone, corticosterone, potassium and renin activity, and urinary potassium excretion, were measured in control (CK) rats, and in rats adapted to a high potassium diet (HK), before and after an acute intragastric KCl load. Prior to the KCl load there was no difference in plasma potassium (K) or plasma aldosterone. Following the KCl load, HK rats maintained a lower plasma K, and, except at 30 min after the load, a lower plasma aldosterone than CK rats. At a low plasma K there was no difference in plasma aldosterone between CK and HK rats. At a high plasma K (greater than 8 mmol/l) the HK rats had a higher plasma aldosterone for the same plasma K than CK rats. The enhanced ability to excrete an acute K load seen in HK rats seems unlikely to be due to higher levels of plasma aldosterone.     

Renin–angiotensin–aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin–angiotensin–aldosterone system (RAAS) may be related to variation in the plasma CETP level. We questioned whether the plasma CETP level would affect RAAS responsiveness to low sodium diet and the blood pressure response to angiotensin-II infusion in healthy subjects. Methods: RAAS parameters and blood pressure were determined during liberal sodium diet (200 mmol/24 h) and low sodium diet (50 mmol/24 h) in 67 healthy men. Blood pressure response to incremental angiotensin-II infusion was assessed in 34 subjects during liberal sodium diet. Correlation analysis was performed to test whether RAAS responsiveness and blood pressure were related to plasma CETP mass, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I measured during liberal sodium diet. Results: CETP mass ranged from 1.29 to 2.95 mg/l. No significant differences in (changes) in mean arterial pressure, aldosterone and active plasma renin concentration in response to low sodium were observed between the lowest and highest tertiles of CETP mass, HDL-C and apolipoprotein A-I. These outcome variables were also not significantly correlated with CETP, HDL-C and apolipoprotein A-I, except for a modest relation of aldosterone measured during low sodium with apolipoprotein A-I (r = 0.28, p = 0.022). Blood pressure response to angiotensin-II was similar between CETP tertiles. Conclusions: Mineralocorticoid and blood pressure responsiveness to dietary salt intake are not significantly related to physiological interindividual differences in plasma CETP. We suggest that a lower CETP mass does not exert adverse effects on blood pressure regulation.     

MODERATE SODIUM RESTRICTION AND POTASSIUM SUPPLEMENTATION IN ESSENTIAL HYPERTENSION

Continuous 24 h arterial blood pressure and vasoactive hormones were measured in twelve patients with essential hypertension after 4 weeks on a control sodium intake (180 mmol/day) and after similar periods of sodium restriction (80 mmol/day) and potassium supplementation (200 mmol/day). Sodium restriction was associated with variable blood pressure changes in individual patients and a small reduction in 24 h mean pressure of 4/3 mmHg. The greatest fall in blood pressure with sodium restriction was seen in those patients with the least rise in renin. Potassium supplementation was associated with variable individual blood pressure changes and a trivial reduction in mean 24 h pressures (0.1/0.8 mmHg). Mean 24 h plasma aldosterone concentration was significantly higher during sodium restricted and potassium-supplemented diets, compared to control levels, but other vasoactive hormones were unchanged.     

Angiotensin-converting enzyme inhibition as a therapeutic principle in Bartter's syndrome

Summary The effect of captopril has been investigated in four patients with Bartter's syndrome treated for 12 weeks.Baseline biochemistry showed normal serum aldosterone (mean 347 pmol·l^–1) and a mean serum renin of 217 mU·l^–1, and a considerable increase in serum renin during captopril treatment. Serum aldosterone decreased gradually during the study period to about half its initial value. The patients presented with a mean serum potassium of 2.5 mmol·l^–1, which rose to 3.4 mmol·l^–1 on captopril. Lymphocytes showed a substantial captopril-induced increase in intracellular sodium (from 15 to 22.5 mmol·l^–1 on average), but no change in the potassium content.Captopril was well-tolerated. It may be an alternative to potassium-sparing diuretics for maintaining normal serum potassium levels in patients with Bartter's syndrome.     

INCREASED RENAL SENSITIVITY TO ALDOSTERONE IN THE RAT: INDUCTION BY A HIGH POTASSIUM DIET

1. The renal response to aldosterone, measured by urinary sodium and potassium excretion, was determined in adrenalectomized rats that had been previously fed either a high potassium diet or a control diet. High K⁺ rats showed an enhanced response to aldosterone at all doses tested. 2. The induction of this enhanced response to aldosterone could be suppressed by a high sodium intake. It may also require the presence of the adrenal glands during the induction period, although interpretation of adrenalectomy experiments in the present study was made difficult by the effect of maintenance DOC therapy on the renal response to aldosterone. 3. The enhanced response could not be induced by a low sodium diet alone or by the administration of high doses of exogenous aldosterone. 4. No difference between high K⁺ and control rats could be detected in rat kidney mineralocorticoid receptors, assessed by both in vivo and in vitro binding of tritiated aldosterone. 5. The method of the induction, and the mechanism of the enhanced response remains to be defined.     

ALTERING ANGIOTENSIN LEVELS BY ADMINISTRATION OF CAPTOPRIL OR INDOMETHACIN, OR BY ANGIOTENSIN INFUSION, CONTRIBUTES TO AN UNDERSTANDING OF ATRIAL NATRIURETIC PEPTIDE REGULATION IN MAN

1. Plasma atrial natriuretic peptide (ANP) levels were positively correlated with plasma renin activity (PRA) levels, when blood volume and blood pressure (BP) were not raised in normal subjects (NLS) or patients with postoperative aldosterone-producing adenoma (APA), Bartter's syndrome (BS), Addison's disease, anorexia nervosa, diuretic abuse or salt-losing congenital adrenal hyperplasia. 2. Angiotensin II infusion raised ANP levels in NLS, and patients with BS, pre- and postoperative APA, only when BP rose, suggesting that this effect might be mediated by the rise in BP. 3. Captopril lowered aldosterone and ANP levels in renal artery stenosis, but falling BP levels could mediate this effect. Captopril lowered aldosterone and BP in BS, but did not lower ANP, perhaps because angiotensin remained elevated. 4. Indomethacin lowered ANP when PRA was initially normal or raised (NLS and BS), but not when PRA was suppressed (APA). This effect could not be mediated by BP, which rose, but could be mediated by renin-angiotensin, which fell. 5. Factors other than central blood volume and atrial stretch may modulate ANP levels. Plasma angiotensin II may be such a factor, and may exert an important influence at high levels, especially when blood volume is low.     

A low molecular weight heparin decreases plasma aldosterone in patients with primary hyperaldosteronism

Summary Four patients with primary hyperaldosteronism were treated with nadroparin 4100 or 6150 antiXa IU daily for 4 days. Plasma and urine sodium and potassium, and plasma aldosterone and renin were monitored before, during and after the study.After four days of treatment, and for the following two days, plasma aldosterone was decreased (by a mean of 49% on Day 6), and urinary Na/K was increased (3.7-fold). The direction of the changes was reversed on Day 8.The study has confirmed the effect of low molecular weight heparin on aldosterone, and makes it unlikely that it is related to inhibition of angiotensin II stimulation in these patients, as renin could not be detected in their plasma.     

IS ALDOSTERONE/RENIN RATIO USEFUL TO SCREEN A HYPERTENSIVE POPULATION FOR PRIMARY ALDOSTERONISM?

The ratio of aldosterone to renin in plasma was measured in samples collected from 79 hypertensive patients. Eighteen patients with primary aldosteronism had ratios ranging from 25 to 677 (mean 183) when measured on 34 occasions, while 16 normal subjects had ratios of 3.3-21 (mean 11.3). Of the remaining 61 patients with ratios ranging from 1.8 to 184, 15 patients have ratios greater than 25 and are under investigation for primary aldosteronism, which appears highly likely in five and has been excluded in two. The aldosterone/renin ratio appears promising as a screening test for primary aldosteronism. Consistency and the effects of sodium and potassium balance and of antihypertensive medications require further study.     

Aberrant Rac1–mineralocorticoid receptor pathways in salt‐sensitive hypertension

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Effect of the aldosterone antagonist canrenone on plasma aldosterone concentration and plasma renin activity,and on the excretion of aldosterone and electrolytes by man

Summary Canrenone was administered in doses of 2×82 mg and 2×164 mg per day over a period of 10 days to diabetic patients without cardiovascular, liver or kidney involvement. Aldosterone excretion and plasma aldosterone increased only slightly during both regimes. There was a clear-cut increase in aldosterone excretion only after discontinuation of carenone. Excretion of sodium potassium and fluid was not significantly changed either during or after treatment. The lack of effect of canrenone on the kidney was in contrast to the significant decrease in serum sodium and increase in serum potassium, and the significant, dose-dependent rise in plasma renin activity following canrenone administration. The increased plasma renin activity persisted for some days after discontinuation of canrenone. It is suggested that canrenone primarily exerted its effect in the distal part of the large intestine where ionic movements are most affected by aldosterone. The disproportionately slight increase in plasma aldosterone concentration and aldosterone excretion, in spite of the greatly elevated plasma renin activity and serum potassium level, is considered to be due to a direct inhibitory effect of canrenone on aldosterone production in the adrenals.     

EFFECTS OF ALTITUDE ON ATRIAL NATRIURETIC PEPTIDE: THE BICENTENNIAL MOUNT EVEREST EXPEDITION

1. Overnight recumbent atrial natriuretic peptide levels were significantly elevated in all ten subjects of the Australian Bicentennial Mount Everest Expedition during the first week at 5400 m, during acclimatization. 2. Twenty-four hour urine volume and urine sodium increased markedly at altitude. 3. Plasma renin activity and plasma aldosterone levels decreased significantly at altitude. 4. No significant changes in plasma cortisol, plasma sodium or potassium, body temperature, systolic or diastolic blood pressure or heart rate were observed. 5. Although it was impossible to control or measure salt and water intake during the study, results suggest that atrial natriuretic peptide may be important in the reduction in renin and aldosterone levels and in the diuresis and natriuresis necessary to adapt to hypoxia at altitude.     

Hypotensive effects of sodium volume depletion and 1-sar-8-ala-angiotensin II in relation to plasma renin in hypertensive patients

Summary The hypotensive effect of acute sodium volume depletion, produced by chlorthalidone and a low sodium diet, was inversely related to the plasma renin concentration (PRC) in 13 hypertensive patients of varying aetiology (r=0.61; p<0.05); weight reduction induced by this therapy was not related to PRC (r=0.12; p>0.1). The angiotensin II antagonist 1-sar-8-ala-angiotensin II failed to reduce arterial pressure when the patients ingested 130 mEq sodium per day, but pressure fell when it was infused during sodium volume depletion, except when PRC remained low; the changes in pressure were related to the plasma renin level (r=0.78; p<0.005). The combined hypotensive response to acute sodium volume depletion and to angiotensin II blockade during sodium volume depletion was not related to PRC (r=0.15; p>0.1). The results demonstrate that acute sodium volume depletion caused similar weight loss in patients with high and low PRC values, and it would have had similar hypotensive effects but for angiotensin-induced vasoconstriction in the high renin patients. Since 1-sar-8-ala-angiotensin II also reduced arterial pressure in 6 patients during chronic diuretic therapy, angiotensin II must still induce vasoconstriction in these circumstances.     

POTASSIUM EXCRETION IN RENAL FAILURE IN THE RAT: THE ROLE OF DISTAL TUBULE FLOW AND ALDOSTERONE

1. This study examines the contribution of an increased distal tubule flow and of aldosterone to the handling of a potassium load in conscious rats with renal failure induced by subtotal nephrectomy or by gentamicin on a control of high K+ diet. 2. Glomerular filtration rate was reduced by subtotal nephrectomy to 40% and by gentamicin treatment to 60% of control. Subtotal nephrectomy induced significant hypertrophy of glomeruli and proximal and distal tubules, but gentamicin did not. Both experimental groups had a normal iothalamate space and plasma potassium after a 20 h fast. 3. Two hours after an acute KCl load rats with renal failure excreted less potassium than control rats. There was also a lesser natriuretic effect of KCl in the renal failure groups. 4. A high K+ diet, given for 5-7 days, increased excretion of an acute KCl load in control rats and rats with renal failure. 5. (UNaV + UKV) was used as an estimate of distal tubule flow. Potassium excretion, related to distal tubule flow, was similar in the renal failure and control rats when on the same diet. This is consistent with potassium excretion being strongly, but not necessarily solely, dependent on distal flow. 6. Adrenalectomy reduced, and aldosterone restored, potassium excretion in the renal failure and control groups. This suggests a role for aldosterone in excretion of an acute potassium load with this degree of renal failure.