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PubMed1976

New mineralocorticoids and adrenocorticosteroids in hypertension.

Alterations in steroidogenesis have been demonstrated in experimental and human hypertension. It is highly likely that increased secretion of the nonaldosterone mineralocorticoid deoxycorticosterone (DOC) and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) may initiate or perpetuate hypertension, or both. It is possible that 16 beta-hydroxydehydroeplandrosterone (16beta-OH-DHEA) directly induces the hypertensive process in animals. The significance of the findings of increased secretion of 16 alpha, 18-dihydroxy-11-deoxycorticosterone (16alpha, 18-diOH-DOC) and dehydroepiandrosterone sulfate (DHEA-S) cannot now be appreciated. Neither has been examined experimentally for its ability to induce hypertension, and the former compound is not a mineralocorticoid. It does possess the curious property of increasing mineralocorticoid activity of other steroids, by altering either their metabolism or mode of action. Variations in the mineralocorticoid hypertensive syndrome or, more aptly, the steroid hypertensive syndrome could account for the hypertension in a substantial portion of patients with reduced plasma renin activity.

18-Hydroxydesoxycorticosterone↗
PubMed1976

Adrenocortical factors in hypertension. I. Significance of 18-hydroxy-11-deoxycorticosterone.

Low renin essential hypertension and the syndrome of mineralocorticoid excess have two features in common, low plasma renin activity and volume-sensitive hypertension. The proposal that both disorders share a common mechanism--because of the ability of agents that inhibit or antagonize the adrenocortical secretion to lower blood pressure in the low renin hypertensive group--appears to be based on a circular argument. The beneficial effect of removal or neutralization of the adrenocortical contribution only constitutes evidence for volume-dependency or sensitivity, which is how the low renin group is defined. Any measure that blocks a component of the normal homeostatic chain for the maintenance of extracellular and intravascular volume including the adrenal cortex would be expected to have a beneficial effect in volume-sensitive hypertension. Evidence for an adrenal factor in low renin hypertension must rest on the isolation of an active substance that reproduces the effect when readministered. 18-Hydroxy-11-deoxycorticosterone (18-OH-DOC) does not meet these criteria. It is not significantly increased in experimental hypertension and, although its overproduction in unselected low renin essential hypertensive patients remains controversial, the magnitude of the reported elevations is insufficient in relation to the low biologic activity of the steroid to account for a significant effect. Apart from its increase in the 17alpha-hydroxylase defect, 18-OH-DOC is increased in primary aldosteronism and may also be an indicator of a histologic variant of the aldosteronoma. On the basis of a large body of evidence showing parallelism between the 11beta- and 18-hydroxylase functions of the fasciculata zone, we have proposed that both enzymic functions are functionally related and may involve the same enzyme protein and catalytic site. According to this view, the secretion of 18-OH-DOC would have no special significance of its own but would be an obligatory consequence of the secretion of fasciculata zone corticosterone.

18-Hydroxydesoxycorticosterone↗
PubMed1977

Urine electrolyte response to 18-hydroxy-11-deoxycorticosterone in normal man.

1. To assess whether the adrenal corticosteroid 18-hydroxy-11-deoxycorticosterone [18-(OH)-DOC] affects urine electrolyte excretion in normal man, seven male volunteers received 120 microgram (353 nmol) intravenously in 1 h. This was compared with glucose (50 g/l; control) and aldosterone (80 microgram, 222 nmol) infusions in the same subjects. 2. A definite though weak antinatriuretic response to 18-(OH)DOC was observed, whereas urine potassium excretion was not altered. Aldosterone increased urine potassium excretion and reduced sodium output. Urine pH was lowered by both corticosteroids, aldosterone in general having a more marked effect. Urine volume was not altered by 18-(OH)DOC. 3. Plasma concentrations of 18-(OH)DOC and aldosterone rose approximately tenfold during their respective infusions. Compared with that of aldosterone, the metabolic clearance rate of 18-(OH)DOC was slower andits plasma half-life was longer. 4. We have been able to demonstrate that 18-(OH)DOC has a definite, albeit weak antinatriuretic action in normal man, but whether or not this corticosteroid is capable of elevating the blood pressure in man remains to be shown.

18-Hydroxydesoxycorticosterone↗
PubMed1975

Effect of intravenous infusion of corticosteroids on blood pressure, electrolytes, and water metabolism in sheep.

ACTH administration (80 IU/day for 5 days), which produces hypertension and charateristic metabolic effects in sheep (38), has been compared with the effect of intravenous infusion of cortisol (5 mg/h), corticosterone (0.5 mg/h), deoxycorticosterone (50 mug/h), and 11-deoxycortisol (1 mg/h), each given singly for 5 days. Further, a mixture consisting of aldosterone (3 mug/h), cortisol (5 mg/h), deoxycorticosterone (25 mug/h), corticosterone (0.5 mg/h), and 11-deoxycortisol (1 mg/h), was also infused intravenously for 5 days. In another series of experiments, 18-hydroxydeoxycorticosterone (100 mg/h) was also included in the combined-steroid solution. With the exception of 18-hydroxydeoxycorticosterone, which was not measured, the rates of infusionproduced peripheral arterial blood levels of the steroids similiar to those seen with ACTH stimulation. Blood pressure,water intake, urine output, and plasma and urinary electrolytes were measured: individual steroids had little effect on these, but manyof the metabolic changes produced by ATCH (hypokalemia and increased water intake andurine output) were produced by the combined-steroid infusion. However, the combined-steroid infusion failed to induce an increase in blood pressure similiar to that seen inthe ACTH experiments. Thus the findings are against a major role in ACTH hypertension for any steroid used, either singly or in combination. As yet unrecgnized factor/s may be involved in the ACTH-induced hypertension.

18-Hydroxydesoxycorticosterone↗
PubMed1976

The regulation of plasma 18-hydroxy 11-deoxycorticosterone in man.

18-hydroxy 11-deoxycorticosterone (18-OH DOC), a weak mineralocorticoid, was estimated by a radioimmunoassay procedure after purification in 49 patients with hypertension and 38 normal control subjects. The sensitivity of the method was 2-4 pg; there was no detectable blank, and the precision was 9-10%. In normal subjects the absolute plasma levels were similar to those of aldosterone. ACTH administration produced a 23-fold increase, and sodium restriction resulted in a 4-fold increase (5.4+/-0.7-20.5+/-3.0 ng/dl). On the other hand, the plasma levels of 18-OH DOC declined by nearly 50% with upright posture or angiotensin II infusion. During both of these procedures, plasma aldosterone levels significantly increased. Patients with normal and low renin hypertension had similar changes in plasma 18-OH DOC levels with sodium restriction. However, the mean high sodium level in the normal renin essential hypertension group (11.6+/-1.6 ng/dl) was significantly greater (P is less than 0.001) than in the control group (5.4+/-0.7 ng/dl). In addition, at least 22% and perhaps as high as 37% of the hypertensive subjects had levels greater than the upper limits of normal on a high sodium intake. Differences between the groups were less impressive in the sodium-restricted studies. There were no significant differences in age, duration of hypertension, sodium balance, serum sodium, potassium, or blood urea nitrogen in those patients who had elevated levels of plasma 18-OH DOC. Patients with primary aldosteronism had levels within the normal range on both dietary intake. However, in contrast to the other groups there were no significant changes in the plasma levels with sodium restriction. Thus, a significant number of patients with essential hypertension presumably have an alteration in 18-OH DOC secretion.

18-Hydroxydesoxycorticosterone↗
PubMed1978

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.

18-Hydroxydesoxycorticosterone↗
PubMed1976

Unusual low plasma renin hypertension in a child.

A four-year-old girl with hypertension (140/60) and chronic hypokalemic alkalosis was studied to determine the origin of this clinical feature. High exchangeable sodium (56.7 meq/kg vs. 45-55 meq/kg in controls) was associated with a low plasma renin activity (6 ng/1/min vs. 26 +/- 3.1 in controls) and reduced aldosterone secretion rate (5.56 mug/day; normal: 50-150 mug per day)). A low corticosterone secretion rate (0.228 mg/day vs. 0.50-0.65 in controls) and urinary tetrahydrodeoxycorticosterone (0.007 mg/day vs. 0.03-0.09 mg/day in controls) were found. The basal secretion rate of cortisol was also low (1.80 mg/m2/day vs. 5.4-16.7 mg/m2/day in controls) in spite of normal plasma ACTH: 78 pg/ml. The normal increase of the cortisol secretion rate (from 1.80 to 65 mg/m2/day) after synthetic ACTH stimulation ruled out a 17 alpha hydroxylase deficiency. The low sweat Na/K ratio (0.25) and the good suppressing efficacy of dexamethasone and of the spironolactones on hypertension and on the hypokalemic alkalosis agreed with the hypersecretion of a mineralocorticoid. The secretion rate of 18 hydroxydeoxycorticosterone was high (91 mug/day/1.73 m2 vs. 40-80 mug per day and per 1.73 m2). As the mineralocorticoid potency of this steroid is weak, we speculate that it might be the precursor of a more potent but unknown mineralocorticoid which could influence the ACTH secretion.

18-Hydroxydesoxycorticosterone↗
PubMed1976

Radioimmunoassay of 18-hydroxy-11-deoxycorticosterone in plasma.

A method is described for the radioimmunoassay of 18-OH-DOC using antibodies generated in rabbits against the carboxymethoxime derivative coupled to bovine serum albumin. The procedure uses 4 ml of plasma with intra and interassay variations of 8 and 9% respectively. Standard 18-OH-DOC added to plasma from an adrenalectomized patient gave a regression equation, Y=0.974X+/-2.210 and a correlation coefficient of 0.999. The only cross reacting steroid, 18-OH-B which may lead to falsely high levels is removed by a single thin layer chromatographic step. Blood levels in normal subjects agree closely with those calculated indirectly by metabolic clearance and secretion rate measurements. ACTH stimulation produced an 18-fold increase in plasma concentration while dexamethasone suppression decreased levels 3-fold. Four hours in the upright position resulted in a decreased plasma concentration while aldosterone increased. No significant response to dietary sodium restriction could be demonstrated.

18-Hydroxydesoxycorticosterone↗
PubMed1976

Corticosterone, 18-OH-deoxycorticosterone, deoxycorticosterone and aldosterone secretion in tissue culture of foetal rat adrenals in the presence and the absence of ACTH.

A method for simultaneous analysis of the main corticosteroids secreted by the rat adrenal is described. Purification is performed using previously established steps involving dichloromethane extraction, ethanol-cyclo-hexane partition and Sephadex-LH-20 column chromatography. Deoxycorticosterone and aldosterone are then quantitated with radioimmunoassay and corticosterone and 18-hydroxy-deoxycorticosterone with gas liquid chromatography as their 0-methyloxime=trimethylsilyl ethers. The coefficient of variation of the method for these steroids in concentrations found in the tissue culture of feotal rat adrenals varies between 3.9-10.9 %. The secretion of these steroids in the tissue culture of foetal rat adrenals is studied. The steroid secretory pattern is correlated with a differentiation stage of the cultures as detected by electron microscopy. The initial secretory activity declines considerably after 15 days of cultivation to a low level. This is the case also with respect to aldosterone although the cortical cell population changed from the mixed population of the differentiated (zona fasciculata-like) and undifferentiated (zona glomerulosa-like) cells to homogenous undifferentiated growth. Addition of ACTH increased deoxycorticosterone secretion rapidly. Corticosterone, 18-hydroxy-deoxycorticosterone and aldosterone secretion was observed only after the differentiation of the cells (especially changes in their mitochondrial compartment) was evident morphologically.

18-Hydroxydesoxycorticosterone↗
PubMed1976

Effects of corticosterone on adrenocorticotrophin-induced mitochondrial differentiation with special reference to 11 beta- and 18-hydroxylation.

The effects of corticosterone in concentrations found in adrenal venous plasma on ACTH-induced changes in cultured cortical cells derived from foetal rat adrenals were studied. Corticosterone at a concentration of 5-7 X 10(-5) mol/l completely inhibited mitochondrial differentiation to fasciculte-like morphology. The same cultures revealed significant inhibition of 11beta- and 18-hydroxylation compared with cultures treated with ACTH only. This was shown by the reduced formation of corticosterone and 18-OH-deoxycorticosterone (48%, P less than 0-001) and simultaneous enhancement of deoxycorticosterone formation (33%, P less than 0-05) from added [4-14C]progesterone. Similar inhibition was observed when dibutyryl cyclic AMP replaced ACTH as an inducer of differentiation. Lower concentrations of corticosterone (1-2 X 10(-5) and 2-4 X 10(-5) mol/l) inhibited ACTH-stimulated formation of corticosterone and 18-OH-deoxycorticosterone from endogenous precursors. The results demonstrate that corticosterone regulates the stage of differentiation in cultured adrenocortical cells. The possible role of corticosterone in the regulation of growth and steroidogenic capacity of the adrenal cortex is discussed.

18-Hydroxydesoxycorticosterone↗