[Arguments for the existence of an endogenous inhibitor of renal Na-K ATPase with steroid structure and natriuretic action].

In order to explain the opposite effect of 6,7-dihydroxylated isomers of 6, 7 - dihydrocanrenone on the urinary sodium and potassium excretion, we have tested the effect of these substances isolated from human urine on the Na(+)-K+ pump from different tissue preparation: rabbit kidney slices as well as NA-K ATPase purified from the kidney. Our results show an inhibition of pump as well as enzyme activity by the 6 beta 7 alpha isomer while the 2 other isomers are either uneffective or slightly stimulating. The 6 beta 7 alpha dihydroxy-6, 7-dihydrocanrenone could be one of the plasma ouabain-like substance incriminated in the pathogenesis of volume-expanded hypertension.

Effect of various 6-dehydro-corticosteroids, 9, 11-dehydro-DOCA and 9 alpha-fluoro-DOCA on the fluxes of sodium and potassium.

The introduction of a double bond at carbons 6 and 7 (6-dehydro-derivatives) of deoxycorticosterone acetate (DOCA), cortisol-21-acetate, 9 alpha-fluorocortisol-21-acetate (9 alpha-F-C-ac) and aldosterone-21-acetate substantially reduces affinity for Type II receptors but not for Type I receptors. Such a modification changes the effect of these steroids on urinary excretion of Na+ and K+. 6-Dehydro-derivatives will thus bind preferentially to receptor Type I inducing the retention of sodium and compete with mineralocorticoids for such receptors.

Identification of biologically active natural spirolactone derivatives in man and animal.

For the first time, the presence of three natural spirolactones hydroxylated at C6C7 (6 alpha, 7 alpha-, 6 beta, 7 alpha- and 6 beta, 7 beta-dihydroxy-6,7-dihydrocanrenone (DHC) is demonstrated in man and in animal urine (rat, dog, sheep), and possibly in the blood. The existence of the fourth isomer 6 alpha, 7 beta- is also possible. Salt-loading in man and the rat results in a decrease in urinary 6 alpha, 7 alpha- and 6 beta, 7 beta-DHC.

Effect of 6-dehydro-DOCA and 6-dehydro-9 alpha-fluorocortisol acetate on the excretion of sodium and potassium in the rat.

Deoxycorticosterone acetate (DOCA) and 9 alpha-fluorocortisol acetate (9 alpha-F-Cac) can be modified by the introduction of a double bond at carbons 6 and 7 (6-dehydro-derivatives). Such a modification markedly changes the effect of the steroids on urinary excretion of Na+ and K+. Since 6-7 reduction of DOCA and 9 alpha-F-Cac substantially reduces affinity for Type II receptors but not Type I receptors, 6-dehydro-derivatives will thus bind preferentially to receptors influencing the retention of sodium (the "mineralocorticoid" or Type I receptor), and compete with mineralocorticoids for such receptors.

Discovery of a natural spirolactone derivative in man and animal.

The presence of 6,7-dihydroxy-6,7-dihydrocanrenone (DHC) in man and in animal has been shown. Sodium loading results in a decrease of urinary DHC. On the contrary, sodium depletion increases its concentration.

Role of hydrophobic effects and polar groups in steroid-mineralocorticoid receptor interactions.

To test whether hydrophobic interactions are the main driving forces in the association of steroids with mineralocorticoid receptors, the binding free energy calculated (delta Gc) using the surface area of the steroids accessible to water was compared with the observed free energy (delta GM) obtained from the Kd at the equilibrium estimated in the rat cytosol. The results are consistent with a binding process involving principally hydrophobic effects implying association of both faces of the steroid with the receptor. The discrepancies between calculated and observed values probably depend upon the mechanism of hydrogen bonding of the polar groups of the steroids to those on the receptor.

[Steroid ligands of androgen binding protein. The enantiomers of trans-trans and cis-trans perhydrohexestrols and trans-trans perhydrodiketones].

In the framework of a study on nonsteroidal androgens, the authors previously observed that in perhydrohexestrol series, the (+/-)-[(cis-4 hydroxycyclohexyl)-4(trans-4 hydroxycyclohexyl)-hexane] or cis-trans perhydrohexestrol and especially the (+/-)-(3,4 bis (trans-4-oxocyclohexyl)-hexane) or trans-trans perhydrodiketone, there is no affinity for AR (androgen receptor of the prostate) but they bind with high and specific affinity to the testosterone binding sites on ABP (epididymal androgen-binding protein). In this work, we describe the preparation, the stereochemistry and biological activities of trans-trans and cis-trans perhydrohexestrols and of trans-trans perhydrodiketone as well as their corresponding enantiomers. Biologically the tests AR and ABP are negative for the trans-trans perhydrohexestrol and of trans-trans perhydrodiketone and for its enantiomers.

Diurnal 18-hydroxy-11-deoxycorticosterone pattern in human stable hypertension.

Diurnal 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) pattern was studied with RIA technique in 33 hypertensive patients in supine position and on normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone and cortisol were measured.

24 hour profile of 18-hydroxy-11-deoxycorticosterone in normal supine man: relationship with cortisol and aldosterone.

Daily profiles of plasma 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) were studied in four normal supine men on a normal sodium intake. Blood was taken every hour from 01.00 to 24.

Radioimmunoassay for aldosterone and deoxycorticosterone in human plasma. Comparison of various antisera and determination of normal values.

This paper describes a study of the physico-chemical and radioimmunological properties of three antialdosterone antisera which permitted practical conclusions to be drawn. By its high degree of specificity, anti-aldo-3-oxime-BSA constitutes the most useful antiserum for the clinical assay of aldosterone. The principal advantage of this antiserum is that it allows both urinary and blood aldosterone radioimmunoassay without the necessity of including a chromatographic step.

Mineralocorticoid like effect of new 18-hydroxy-steroid isolated from urine of hypertensive patients.

The affinity of new urinary 18-hydroxy-steroid (Cp x) for mineralocorticoid receptors was estimated. When rat kidney slices were incubated with 2 x 10(-9) M 3H-aldosterone, Cp x (2 x 10(-5) M) was able to compete with aldosterone for the mineralocorticoid cytosol receptors. Cp x had low but significant affinity for mineralocorticoid receptor sites.

18-hydroxylated steroids in human hypertension - clinical study.

The detection of two unknown urinary steroids called x and y in various patients was previously reported. Compound x was tentatively characterized as a derivative of dihydro-18-hydroxy-DOC with two additional polar groups. In this communication clinical observations of a set of 25 hypertensive patients are presented.