Low Renin Essential Hypertension Research Articles

The Metabolic Clearance of Aldosterone Decreases Similarly during Infusion of Angiotensin II in Patients with Essential Hypertension and in Normal Subjects*

To determine if the abnormally large increases in levels of plasma aldosterone which occur during infusion of angiotensin II in some patients with essential hypertension are due to abnormal decreases in the metabolic clearance of aldosterone, we measured clearances of aldosterone before and during infusion of angiotensin II in 12 patients with essential hypertension and in 10 normal subjects. The metabolic clearance of aldosterone in the patients and that in the normal subjects were the same before angiotensin II was infused and the clearances decreased similarly during infusion of angiotensin II. In agreement with our previous observations, the plasma aldosterone responses to angiotensin II were greater than normal in most of the patients with low renin essential hypertension. Thus, the brisk increases in levels of plasma aldosterone during infusion of angiotensin II in patients with essential hypertension reflect abnormally large increases in the secretion of aldosterone. These results add further support to the idea that adrenal sensitivity to angiotensin II is increased in some patients with essential hypertension.

Specific binding of [ 3H]-16β-hydroxydehydroepiandrosterone by rat kidney

16β-Hydroxydehydroepiandrosterone (16β-OH-DHEA) can influence electrolyte excretion in the rat and has been reported to be elevated in the urine of patients with low-renin essential hypertension. This steroid does not bind to the mineralocorticoid receptors in rat or human kidney that bind aldosterone and other sodium-retaining steroids. Thus, actions of 16β-OH-DHEA may be mediated through other binding sites. To obtain a direct indication of how cells interact with 16β-OH-DHEA, we studied the binding of the radioactively labeled steroid. Limited capacity binding of [ 3H]-16β-OH-DHEA was demonstrated after incubating the steroid with kidney slices at 37°C (apparent equilibrium dissociation constant ( K D approximately 0.3 μM) or cytosol at 0°C ( K D approximately 3 μM). Specific binding activity by kidney cytosol was respectively 6-fold and 40-fold greater than by liver or brain cytosol. Nonradioactive testosterone, progesterone and the spironolacton SC14266 had detectable but weak activities (as compared with non-radioactive 16β-OH-DHEA) for inhibition of [ 3H]-16β-OH-DHEA. No significant competition was observed with androstenediol, aldosterone, deoxycorticosterone, corticosterone and 16-oxo-androstenediol at concentrations to 10 μM. A heat-dependent nuclear transfer mechanism for 16β-OH-DHEA was not observed. Thus, limited capacity binding sites exist in rat kidney which can recognize 16β-OH-DHEA. The sites are distinguishable from the previously characterized mineralocorticoid, glucocorticoid and androgen receptors, and differ from known steroid receptors in that they lack an obvious nuclear transfer mechanism. The physiological role of the binding sites detected in these studies is not known.

Enhanced Adrenal Responsiveness to Angiotensin II in Patients with Low Renin Essential Hypertension*

The plasma aldosterone response to infused angiotensin II was determined in normal controls and in patients with normal renin and with low renin essential hypertension. The patients with low renin essential hypertension showed an enhanced plasma aldosterone response when compared to the other two groups. This finding may explain why plasma aldosterone levels remain within normal limits in the face of suppressed plasma renin and angiotensin II concentrations in low renin essential hypertension.

Sympathetic nerve activity in low renin essential hypertension.

In order to clarify the properties of sympathetic nerve activity in low renin essential hypertension, plasma catecholamines (CA), dopamine-β-hydroxylase (DBH) activity and urinary CA were measured and the changes of these variables induced by 60° head-up tilt or i.v. injection of tyramine (0.1 mg/kg) were also measured in in-patients with low renin (LRH) and normal renin essential hypertension (NRH). IN addition, blood pressor response to tyramine, i.v. infusion of 0.3 μg/kg/min. of noradrenaline (NA Response) and 0.015 μg/kg/min. of angiotensin-II (ANG-II Response) were determined before and after salt restriction (Na 35, K 75 mEq) for 7 days or salt loading (Na 390, K 75 mEq) for 14 days. The basal values of plasma noradrenaline (NA), plasma DBH, and 24 hour urinary excretion of NA in LRH were significantly lower than in either NRH (p < 0.01, 0.05 and 0.01, respectively) or normotensive subjects (p < 0.05, 0.05 and 0.001, respectively). Plasma NA, plasma DBH and urinary output of NA clearly rose after 30 min. to two hours of the tilt in both LRH and NRH, and the maximal values of plasma NA (p 0.05) during tilting was significantly lower in LRH compared with those in NRH, while no significant difference was observed in the changes of plasma DBH and urinary NA between LRH and NRH. Following i.v. injection of tyramine, the maximal value of plasma NA and blood pressure rise was significantly lower (p 0.05) and significantly higher (p 0.05) than those in NRH, respectively. Following salt restriction, significant reduction of mean arterial pressure (MAP), pressor response to NA and ANG-II and a marked augmentation of PRA and urinary NA were observed. LRH showed a more marked reduction of MAP (p 0.01) and of NA Response (p 0.05) and a significantly higher augmentation of urinary NA excretion (p 0.05) than those in NRH. The increase of PRA (p 0.02) and the decrease of ANG-II Response (0.05 p 0.1) were less in LRH than in NRH. On the other hand, following salt loading, LRH exhibited a significant elevation of MAP and diminution of urinary NA, which differed markedly (p 0.01 and p 0.001) from those in NRH, in whom no significant changes were observed. No significant difference was observed between LRH and NRH in the other variables. These findings suggest that, in LRH, there exists a reduced sympathetic nerve activity at rest and a suppressed sympathetic responsiveness to the postual and tyramine stimulation, and these reduced sympathetic activity might be not primary but rather secondary to the changes in water-sodium balance.

Evidence for Heterogeneity of Mineralocorticoids in Urine of Patients with Low Renin Essential Hypertension*

Mineralocorticoid activity in urine of seven patients with low renin essential hypertension and in five normal subjects was evaluated. Urine was collected during continuous treatment with small doses of dexamethasone, which largely eliminated ACTH-dependent steroids without altering blood pressure. Free (unconjugated) steroids were extracted from urine. Urine was then acidified (pH 1.0) and reextracted for conjugated steroids. Extracts were then fractionated using LH-20 columns and high pressure liquid chromatography. The nine fractions thus obtained were subjected to bioassay in adrenalectomized rats, using a decrease in Na to K ratio as the index of mineralocorticoid activity. Aldosterone appeared in fraction 2, corticosterone in fraction 4,11-deoxycorticosterone in fraction 6, and progesterone in fraction 8. In patients with low renin essential hypertension, free unknown mineralocorticoids were excreted in fraction 5 (cases 1–3), in fraction 6 (cases 1, 2, and 4), in fraction 7 (cases 1 and 4), and in ...

Body fluid balance and fractional excretions of sodium, inorganic phosphorus, potassium and free water in low renin essential hypertension.

Plasma volume (PV), extracellular fluid volume (ECFV) and total exchangeable sodium (Nae) were measured by the dilution methods of 131RISA and 22NaCl in the patients with low-(LRH), normal-(NRH) and high-renin essential hypertension (HRH). In addition, fractional excretion of sodium (FENa) and inorganic phosphorus (FEP) and free water (FEW), urinary Na/K ratio after oral water ingestion of 400 ml/m2 body surface area, and fractional potassium excretion (FEK) after intravenous injection of 80 ml of 10% sodium thiosulfate, estimated by clearance method, were compared between LRH and NRH. PV, ECFV and Nae, which inversely correlated with logarithm of supine plasma renin activity (log PRA), were significantly higher in LRH than each of NRH and of HRH. FENa and FEP, which are assumed to reflect the renal tubular and proximal tubular sodium reabsorption, were positively correlated with age, severity of hypertension (VA score), mean arterial pressure (MAP) and correlated inversely with endogenous creatinine clearance (Ccr). FENa was also correlated positively with log PRA and negatively with ECFV and Nae in the whole patients with essential hypertension. Twenty-four hour urinary kinins excretion and plasma levels of antidiuretic hormone (ADH) measured by radio immunoassay were compared between LRH and NRH. LRH had significantly lower FENa and FEP than age-, MAP- and Ccr-matched NRH and lower urinary excretion of kinins than age-matched NRH. The mean values of these variables in LRH are almost similar to those in normotensive subjects. Plasma ADH levels and FEW were significantly lower and tended to be lower than those in NRH, respectively. Urinary Na/K ratio and FEK which may reflect the mineralocorticoid action on the renal tubule were not significantly different among these three renin sub-groups.

A Study on the Mechanism of Aldosterone Secretion in Low-Renin Essential Hypertension

A Study on the Mechanism of Aldosterone Secretion in Low-Renin Essential Hypertension

Low-Renin Essential Hypertension With Particular Reference to the Effects of Anti-hypertensive Agents

Low-Renin Essential Hypertension With Particular Reference to the Effects of Anti-hypertensive Agents

Effect of aminoglutethimide on blood pressure and steroid secretion in patients with low renin essential hypertension.

An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117+/-2 (mean+/-SE) mm Hg to 108+/-3 mm Hg after 4 days of aminoglutethimide therapy and further to 99+/-3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6+/-7.2 kg in the control period to 80.6+/-7.0 kg after 4 days of drug treatment and to 80.1+/-6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16beta-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16beta-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62+/-0.5 (mean+/-SE) in the control period to 0.9+/-0.2 mug/24 h after 4 days and to 1.1+/-0.3 mug/24 h at the termination of aminoglutethimide treatment. The gradual lowering of blood pressure and body weight during aminoglutethimide therapy is consistent with the view that the antihypertensive effect of the drug is mediated through a reduction in the patients' extracellular fluid volume, probably secondary to the persistent decrease in aldosterone production. The observation that chronic administration of aminoglutethimide lowered blood pressure in these patients and elevated their plasma renin activity to the normal range without decreasing production of the adrenal steroids, deoxycorticosterone, 18-hydroxydeoxycorticosterone, and 16beta-hydroxydehydroepiandrosterone, makes it unlikely that these steroids are responsible either for the decreased renin or the elevated blood pressure in patients with low renin essential hypertension.

Adrenal scintigraphy in low renin essential hypertension.

Adrenal scintigraphy was performed on 23 patients with low renin essential hypertension (LREH). After baseline scintigraphy was shown not to be helpful, 13 of these 23 patients underwent dexamethasone suppression adrenal scintigraphy. Four adrenal imaging patterns were observed: unilateral imaging with adenoma; bilateral early or late imaging with hyperplasia; no uptake with normal adrenals. These imaging patterns were shown to be predictive of the individual patient's response to spironolactone administration of functional adrenal cortical abnormalities in LREH supplies direct evidence for the hypothesis that LREH has an adrenal mineralocorticoid etiology.

Plasma dehydroepiandrosterone sulfate concentration in essential hypertension

Plasma dehydroepiandrosterone sulfate (DS) concentration has previously been reported to be elevated in hypertensive Japanese men with uncharacterized renin status. Indirect evidence suggests that some patients with low renin essential hypertension might be expected to have an elevated plasma DS concentration. The intravenous furosemide test was utilized to categorize renin status in black and white, male and female hypertensive patients, and plasma DS concentration was measured. Plasma DS concentration in the low and normal renin subgroups did not differ significantly. In addition, no difference in plasma DS concentration was noted between black and white hypertensive patients and normal subjects, though plasma DS concentration decreased with age and was lower in women. We thus conclude that plasma DS concentration is normal in the great majority of patients with essential hypertension.

Urinary kallikrein excretion and plasma renin activity in patients with essential hypertension and primary aldosteronism.

1. The 24 h urinary excretion of kallikrein has been studied in 40 normotensive control subjects and in 74 age-matched patients with essential hypertension under similar conditions. By use of the renin-sodium index, hypertensive patients were divided into two subgroup: low-renin hypertension and normal-renin hypertension patients. Urinary kallikrein determinations were also obtained from six hypertensive patients with primary aldosteronism. 2. Urinary kallikrein was significantly lower both in patients with normal-renin and low-renin essential hypertension. Urinary kallikrein excretion was very high in the patients with primary aldosteronism. 3. In nine hypertensive patients beta-adreno-receptor-blocking therapy caused a significant decrease of plasma renin activity, but had no significant effect on urinary kallikrein excretion. 4. The results support the concept that low urinary kallikrein is likely to be a marker of essential hypertension. Under certain conditions its excretion is positively related to mineralocorticoid hormone concentrations but it is not primarily related to the renin-angiotensin system.

Increased adrenal sensitivity to angiotensin II in low-renin essential hypertension.

Studies were undertaken to determine if the dissociation of aldosterone and plasma renin activity in low-renin essential hypertension is due to altered adrenal responsiveness to angiotensin II. The responsiveness of the adrenal glands to angiotensin II was determined by infusing graded doses of angiotensin II into normal subjects and into patients with essential hypertension and measuring changes in levels of plasma aldosterone in response to the infusion. To minimize the influence of endogenous angiotensin II and ACTH, supplemental sodium and dexamethasone were given before the infusions. Levels of plasma aldosterone and plasma renin activity were determined in normal subjects and in the same patients after the combined stimuli of furosemide and upright posture, a maneuver used to increase the level of endogenous angiotensin II. To determine if the changes in levels of plasma aldosterone during infusion of angiotensin II were due to alteration of the metabolic clearance of aldosterone, the metabolic clearance of aldosterone was measured before and during the infusion of angiotensin II. After sodium loading, dexamethasone treatment, and supine posture, levels of plasma aldosterone of normal subjects and patients with essential hypertension were suppressed equally. In response to the infusion of angiotensin II, the levels of plasma aldosterone of patients with low-renin essential hypertension were significantly higher than those of normal subjects or of patients with normal-renin essential hypertension. After furosemide and upright posture, levels of plasma aldosterone of patients with low-renin essential hypertension were significantly higher than those of patients with normal-renin essential hypertension, despite a blunted response in plasma renin activity of the patients with low-renin essential hypertension. Decreases in metabolic clearance of aldosterone during infusion of angiotensin II were similar in patients with normal-renin essential hypertension and in patients with low-renin essential hypertension and accounted for only a small fraction of the marked increase in levels of plasma aldosterone of patients with low-renin essential hypertension. It is concluded that patients with low-renin essential hypertension have increased adrenal sensitivity to angiotensin II. This increased sensitivity may explain the dissociation of aldosterone and plasma renin activity in low-renin essential hypertension.

The pressor response to angiotensin II in patients with low renin essential hypertension.

The etiology of low renin essential hypertension (LREH) has not been established with certainty, but mineralocorticoid excess has been implicated frequently in its pathogenesis. The finding of several investigators of a normal exchangeable sodium space and extracellular fluid volume, however, does not support this hypothesis. To evaluate the possible role of sodium and water retention in LREH, the pressor response to infused angiotensin II (A II) was determined and compared to that of normal subjects and that of subjects with normal renin essential hypertension (NREH). This approach was based on the known suprasensitivity of vascular receptors to A II in situations in which sodium and water compartments are expanded as they are, for example, in proven hypermineralocorticoid states such as primary aldosteronism. In this study, we found that subjects with LREH demonstrated no increased pressor response to graded doses of A II; this suggests that LREH is not primarily mediated by sodium and water retention.

Plasma Aldosterone Response to ACTH in Primary Aldosteronism and in Patients with Low Renin Hypertension*

ACTH alpha 1-24 was infused at incremental rates of 12.5-200 mIU/30 min in dexamethasone-suppressed hypertensive patients on a regular sodium diet. The plasma aldosterone response to this stimulus in 8 patients with hyperaldosteronism due to an adrenal aldenoma and 11 with adrenal hyperplasia was significantly greater at all infusion rates (P less than 0.05) when compared with the response in 6 normal subjects on a similar diet. This responsiveness to ACTH in the patients with primary hyperaldosteronism was similar to that of the normal subjects on a low sodium diet. Twelve patients with low renin and 6 patients with normal renin essential hypertension were similarly studied. There was no significant difference in the median aldosterone response between these 2 groups and the normal subjects on a normal diet, but the response was significantly lower compared with that in patients with primary hyperaldosteronism. These data show that patients with hyperaldosteronism from an adrenal adenoma or hyperplasia have a consistent and exaggerated response to ACTH. The hyper-responsiveness is not apparently shared by the majority of patients with low renin essential hypertension and does not support the concept that this group is an intermediate form of primary aldosteronism. Individual patients within this group, however, may have such a response and might be identified by this type of testing.

Relationship of Basal Plasma Noradrenaline to Blood Pressure, Age, Sex, Plasma Renin Activity and Plasma Volume in Essential Hypertension

1. The relationship of basal plasma noradrenaline to blood pressure, age, sex, urinary sodium excretion, and plasma volume has been examined in 117 untreated ambulatory patients with essential hypertension. 2. No significant correlations between basal plasma noradrenaline and either age or sex were apparent in the total group of essential hypertensive patients. In addition, no significant correlations were observed between plasma noradrenaline and 24 h urinary sodium excretion. 3. Basal plasma noradrenaline concentration was significantly higher in high renin essential hypertensive subjects compared with those with normal or low plasma renin activity. 4. Plasma noradrenaline was reduced significantly in relatively young patients with low renin essential hypertension, but appeared to be normal in other low renin subjects. 5. Basal plasma noradrenaline correlated significantly with blood pressure in patients with normal or low renin essential hypertension but the relationships were only significant in male patients. 6. No significant relationship between basal plasma noradrenaline and either blood pressure or plasma volume could be demonstrated in this population of essential hypertensive patients.

Effects of Prazosin on Blood Pressure and Plasma Renin Activity in Man

1. The effects of oral administration of 4.5 mg of prazosin/day on blood pressure and on plasma renin activity were assessed in patients with essential hypertension and in healthy normotensive volunteer subjects. 2. Mean blood pressure in the hypertensive group fell significantly within 2 weeks of treatment, whereas heart rate was little affected. None of the parameters measured in the normotensive subjects during treatment with prazosin revealed significant changes. 3. Sub-classification of the hypertensive patients into low-, normal- and high-renin categories revealed significant decreases of renin in all six patients with high renin- and in four out of 12 patients with normal renin- but not in the two patients with low renin-essential hypertension. 4. The results indicate the prazosin exerts its hypotensive action and suppresses plasma renin activity particularly in patients with high renin-essential hypertension. These may be considered to have increased sympathetic drive. 5. Conceivably, the blood pressure-lowering effect of prazosin is affected by peripheral vasodilatation and also by a decreased venous return to the heart.

Mineralocorticoid radioreceptor assay: Application to adrenal-regeneration hypertension

Identification of unknown hormones has traditionally involved utilizing a bioassay to initially detect the hormone and to follow its purification. However, radioreceptor assays may be more useful for this purpose by offering greater sensitivity and precision. A mineralocorticoid radioreceptor assay has been developed for use in conjunction with chromatographic separation of a urinary extract to detect the presence of unknown urinary mineralocorticoids. This assay utilizes competition of the unknown steroid and aldosterone for rat renal cytoplasmic mineralocorticoid receptors to enable mineralocorticoid quantitation in aldosterone equivalents. This assay provides 100 fold increase in sensitivity and a significant increase in precision over the commonly used adrenalectomized rat bioassay. The mineralocorticoid radioreceptor assay has been utilized to assay mineralocorticoid activity in chromatographic fractions of a urinary extract from rats with regenerating adrenals. A large area of mineralocorticoid radioreceptor activity has been identified which possibly represents an unknown mineralocorticoid contributing to the etiology of adrenal regeneration hypertension. This assay is applicable to other syndromes of postulated unknown mineralocorticoid excess, such as human low renin essential hypertension. In addition, similar radioreceptor assays are applicable for the initial detection of any type of hormone activity and for the subsequent purification and identification of this hormone.

The C19-mineralocorticoids in hypertension.

The excretion rates of the C19-mineralcorticoids, 16beta-hydroxy-DHEA and 16-oxo-androstenediol, were measured in subjects with low-renin essential hypertension and toxemia of pregnancy. C19-mineralocorticoid excretion in low-renin essential hypertension ranged from 70-790 microgram per day. No significant difference in 16beta-hydroxy-DHEA and 16-oxo-androstenediol excretion was found between these subjects and normal controls. Subjects with toxemia of pregnancy excreted between 350 and 2500 microgram per day of these steroids. There was no significant difference between toxemic and normal pregnancy. Thus, 16beta-hydroxy - DHEA and 16-oxo-androstenediol probably do not play an important role in either low-renin essential hypertension or toxemia of pregnancy.

Saralasin infusion in the recognition of renovascular hypertension.

Saralasin, an angiotensin II antagonist, was infused into 49 patients with renal artery stenosis, 10 patients with essential hypertension and normal renal arteriograms, and five patients with "low-renin essential hypertension." Renal venous renin and differential renal function studies were used to assess the functional significance of arterial stenoses. "Response" to saralasin, evidenced by a fall in blood pressure during infusion, occurred in no patients with "low renin" hypertension and in only 20% of patients with normal renal arteriograms. In contrast, saralasin "response" occurred in more than 80% of patients with renal artery stenosis and lateralizing functional studies and 100% of cases of "proven" renovascular hypertension (cure or improvement of hypertension after operative treatment). We suggest that saralasin infusion might be a valuable screening test for the recognition of renovascular hypertension.