Activation of aldosterone secretion in primary aldosteronism.

Angiotensin infusion evokes marked increases in aldosterone secretion in primary aldosteronism and little change in secondary aldosteronism. The low plasma renin activity of primary aldosteronism and the elevated plasma renin activity of secondary aldosteronism are thought to account for this differential response. The effect of angiotensin on aldosterone and 18-hydroxycorticosterone secretion was studied during adrenal vein catheterization in seven patients with primary aldosteronism (whose plasma renin activity had been elevated following spironolactone therapy), one hypertensive patient with normal plasma renin activity and normal aldosterone secretion, two patients with secondary aldosteronism who had elevated plasma renin activity, and one anephric patient whose plasma renin activity was 0. Adrenal venous aldosterone and 18-hydroxycorticosterone were measured before and after a ten min sub-pressor angiotensin infusion. The cells of the aldosterone-producing adenoma (APA) respond to small increases in plasma angiotensin with large increases in secretion of aldosterone and 18-hydroxycorticosterone. The dose of angiotensin capable of evoking this response from the aldosterone-producing adenoma produces little or no change in the secretion of the steroids from nontumorous glands. The augmentation of aldosterone secretion, induced by angiotensin, in primary aldosteronism is due solely to increased secretion by the adenoma and not by the contralateral zona glomerulosa. The increased sensitivity of the aldosterone-producing adenoma is characteristic of the tumor. This response is independent of fluctuations in endogenous plasma renin activity. This sensitivity is not blunted by high plasma renin activity, nor is it a function of tumor mass for the effect is observed in aldosterone-producing adenomas regardless of size. ACTH injection after angiotensin infusion resulted in a marked increase in aldosterone concentration in the effluent from the nontumorous adrenal, but was not capable of producing further increases in aldosterone concentration in the effluent from the APA. In view of this exquisite sensitivity to infused angiotensin, it may be that the small variations in endogenous plasma renin activity that have been observed in primary aldosteronism may be capable of evoking large changes in aldosterone secretion in patients with aldosterone-producing adenomas.

The critical role of the adrenal gland in the renal regulation of acid-base equilibrium during chronic hypotonic expansion. Evidence that chronic hyponatremia is a potent stimulus to aldosterone secretion.

Recent studies have shown that chronic hypotonic volume expansion (HVE) induced by administration of vasopressin and water stimulates distal hydrogen ion secretion and thereby (a) permits dogs with HCl-acidosis to restore acid-base equilibrium to normal despite continued acid feeding and (b) permits normal dogs to conserve filtered bicarbonate quantitatively despite the natriuresis induced by water retention. To examine whether these effects of chronic HVE are mediated by augmented mineralocorticoid secretion, urinary and plasma aldosterone levels were monitored during prolonged administration of vasopressin. In HCl-fed animals, the HVE-induced rise in plasma [HCO3] (from 13.8 to 21.3 meq/liter) was associated with a rise in aldosterone excretion from 0.45 to 0.88 mug/day (P less than 0.02). In normal animals, in which plasma [HCO3] remained stable during HVE (21.9 vs. 20.0 meq/liter), aldosterone excretion rose from 0.51 to 2.28 mug/day (P less than 0.02) and plasma aldosterone concentration rose from 8.1 to 39.8 ng/100 ml (P less than 0.01). Vasopressin and water were also administered to adrenalectomized animals maintained on glucocorticoids and a slightly subphysiologic replacement schedule of mineralocorticoids. In the HCl-fed adrenalectomized group, plasma [HCO3], instead of rising to normal, showed no significant change (16.9 vs. 15.0 meq/liter). In the non-HCl-fed adrenalectomized group, plasma [HCO3], rather than remaining stable, fell significantly (20.3 vs 16.5 meq/liter, P less than 0.1). Two conclusions can be drawn from this study: (a) the well-known inhibitory effect of volume expansion on aldosterone secretion can be overridden by a potent stimulatory effect on the adrenal produced by severe chronic hypotonicity, and (b) the response of plasma [HCO3] observed during severe chronic HVE is mediated by augmented mineralocorticoid secretion. These findings, furthermore, offer a possible explanation for the puzzling observation that plasma [HCO3] in patients with the syndrome of inappropriate antidiuretic hormone secretion is maintained at normal levels even in the face of severe hyponatremia.

Plasma immunoreactive gamma melanotropin in patients with idiopathic hyperaldosteronism, aldosterone-producing adenomas, and essential hypertension.

A non-ACTH aldosterone-stimulating factor(s) has been implicated in the pathogenesis of idiopathic hyperaldosteronism (IHA). Although this factor has not been fully characterized, some evidence suggests that it may be related to a pro-gamma-melanotropin (pro-gamma-MSH), derived from the NH2-terminal region of pro-opiomelanocortin. In the present study, plasma immunoreactive (IR-) gamma-MSH levels at 0800 h in patients with IHA were evaluated (90 +/- 17 fmol/ml; range: 13-173 fmol/ml) and found to be significantly higher (P less than 0.05) than those in subjects with aldosterone-producing adenomas (33 +/- 8 fmol/ml), essential hypertension (33 +/- 6 fmol/ml), and normotensive controls (19 +/- 2 fmol/ml). Seven of nine IHA subjects had circulating IR-gamma-MSH levels above the normal range (greater than 35 fmol/ml). In plasmas sampled at 1200 h, IR-gamma-MSH was significantly higher in patients with IHA (95 +/- 26 fmol/ml) and adenomas (63 +/- 23 fmol/ml), as compared with essential hypertensives (31 +/- 6 fmol/ml) and normotensives (19 +/- 3 fmol/ml). Mean plasma IR-ACTH, plasma cortisol, and urinary cortisol levels did not differ significantly between any of these groups. In order to evaluate the effect of a pro-gamma-MSH in vitro, adrenal adenoma tissue was obtained from two patients, one with elevated IR-gamma-MSH (61 fmol/ml) and a second with low IR-gamma-MSH (12 fmol/ml). Aldosterone secretion by dispersed adenoma cells from the former, but not the latter, underwent a fourfold dose-dependent (10(-14)-10(-9) M) increase in response to human Lys-gamma 3-MSH. These data suggest that a pro-gamma-MSH may be implicated as a pathogenic factor in a subset of patients with primary aldosteronism, particularly among those differentially diagnosed as having IHA.

Abnormal results of dexamethasone suppression tests in nondepressed patients with diabetes mellitus.

To investigate the specificity of the dexamethasone suppression test (DST) for the diagnosis of major depression in patients with diabetes mellitus, we administered 1 mg of dexamethasone to 30 nondepressed diabetics and to 58 normal controls at 11 PM. Diabetic subjects received hemoglobin A1 (Hb A1) determinations, the Hamilton Rating Scale for Depression (HRSD), and five to eight blood glucose determinations during the 48 hours surrounding the DST. Results demonstrated a significantly higher rate of nonsuppression (plasma cortisol level, greater than or equal to 5 micrograms/dL) at 4 PM the following day among diabetics (43%) than among controls (7%) but no difference between these groups in the rate of nonsuppression at 8 AM. Plasma cortisol level at 4 PM correlated with Hb A1 level but not with duration of illness, HRSD score, mean blood glucose level, or maximum blood glucose excursion. These results suggest that the results of the DST used as a diagnostic test for major depression must be interpreted with caution in patients with diabetes.

Experimental hypertension induced by 19-nor-progesterone treatment in the rat.

Fifty-day-old unilaterally nephrectomized and 1% saline-drinking Sprague-Dawley CD male rats were divided into three comparable groups on the basis of blood pressure, body weight, and fluid intake. The control group received vehicle only, the second group received 19-nor-progesterone [19-nor-pregn-4-ene-3,20-dione (19-Nor-Prog)] in a dose of 250 micrograms/24 h, and the third group received aldosterone-acetate (Aldo-Ac) in a dose of 125 micrograms/24 h, by means of Alzet osmotic minipumps implanted sc for 21 days. Both the 19-Nor-Prog- and the Aldo-Ac-treated rats became hypertensive to a similar degree in the course of the study. Rats given Aldo-Ac also developed polydipsia, decreased body weight, cardionephromegaly, and hypokalemia. The 19-Nor-Prog-treated rats showed no significant changes in heart and kidney weights. The hypertensinogenicity of 19-Nor-Prog is unrelated to significant changes in heart and kidney weight, as is the case with potent mineralocorticoids.

Adrenal steroidogenesis in the spontaneously hypertensive rat (SHR).

Adrenal vein catheterizations were done in SHR and control rats at different ages during the development of hypertension. All SHR became hypertensive by 15 weeks of age. The secretion rate of aldosterone was significantly reduced at 8 weeks of age, 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) at 12 weeks of age, deoxycorticosterone (DOC) at twenty weeks of age, and corticosterone (B) at 12 and 20 weeks of age. Secretion data suggest either an enzyme block, or increased conversion of known steroids to an unknown steroid product. Reduced secretion of corticosterone could explain the adrenal hyperplasia observed in SHR which may be important to the development of hypertension in these animals.

Adrenal steroidogenesis in methylandrostenediol-induced hypertension.

Adrenal vein catheterizations were done in rats made hypertensive by administration of methylandrostenediol (MAD; 17alpha-methyl-5-androstene-3beta,-17beta-diol), and in control rats at intervals during treatment. All MAD-treated rats were hypertensive by 7 weeks. Secretion of corticosterone was consistently decreased at all times in MAD-treated rats. 18-Hydroxy-11-deoxycorticosterone secretion and 11-deoxycorticosterone (DOC) secretion decreased and increased, respectively, compared to controls at 2, 4, and 6 weeks. Aldosterone secretion was decreased at 2 and 4 weeks. This study shows an in vivo block of adrenal 11- and 18-hydroxylation. Transient DOC accumulation by treatment with MAD produced hypertension, though DOC oversecretion and other changes in steroidogenesis were waning by the time hypertension developed.

Role of adrenal steroidogenesis in etiology of hypertension in the spontaneously hypertensive rat.

We measured peripheral adrenal steroid levels in spontaneously hypertensive rats (SHR), killed by nitrogen suffocation, at different ages during the development of hypertension. SHR became hypertensive by 8 weeks of age. Circulating plasma aldosterone (Aldo) levels of SHR gradually declined with age compared to their male Wistar-Kyoto (WKY) normotensive controls. On the other hand, corticosterone (B) concentrations rose relatively as the rats grew older, however, they were significantly lower in SHR at 16 weeks of age. Deoxycorticosterone (DOC) levels were significantly lower at 8 weeks and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) were lower at 16 weeks of age. Steroid ratios at age 4 weeks showed significantly higher B to 18-OH-DOC and lower B to DOC, 18-OH-DOC to Aldo, and 18-OH-DOC to DOC values in SHR. Furthermore, the B to 18-OH-DOC ratio remained significantly higher at 12 weeks and the B to DOC ratio remained lower at 16 weeks. These data imply the possibility of the secretion of an unknown steroid(s) and the existence of another, fourth pathway of Aldo biosynthesis in young SHR. Thus, major alterations of adrenal steroidogenesis exist in young SHR which may be causative in the development of hypertension. After the onset of hypertension, steroidogenesis tends to return to normal, by which time, however, SHR may have developed metacorticoid hypertension.

19-nor-deoxycorticosterone excretion in rats bred for susceptibility and resistance to the hypertensive effects of salt.

Rats susceptible (S/JR) and resistance (R/JR) to the hypertensive effect of salt were weaned at 28 days of age and placed on a high salt intake. Blood pressure, measured at 4-5 and 8-9 weeks of age (after 5 weeks of high salt intake), demonstrated a slight increase in R/JR rats and a highly significant increase in S/JR rats. Urinary fee 19-nor-deoxycorticosterone (19-nor-DOC) levels measured in weekly urine collections were found to be markedly elevated in S/JR rats compared to levels in R/JR rats. Since 19-nor-DOC has been shown to be a potent mineralocorticoid, the results suggest that elevated production of 19-nor-DOC may have a role in hypertension in rats susceptible to the hypertensive effects of salt.

19-Nor-deoxycorticosterone metabolism by rat adrenal glands: evidence for the formation of 19-nor-corticosterone and 19-nor-18-hydroxydeoxycorticosterone.

Incubation of rat adrenal homogenates with tritiated and unlabeled 19-nor-deoxycorticosterone yielded, in addition to unconverted starting substrate, two major radioactive conversion products. These two products were purified by TLC and HPLC and subjected to mass spectrometry and nuclear magnetic resonance analysis. The interpretation of the spectra was consistent with the structures to be 19-nor-corticosterone and 19-nor-18-hydroxydeoxycorticosterone. The possible biological significance of these two compounds is discussed.

Biphasic 19-nor-deoxycorticosterone excretion after adrenal enucleation is associated with altered adrenal mitochondrial cytochrome P450 11 beta-, 18-, and 19-hydroxylase activities.

After adrenal enucleation (AE) rats avidly retain sodium (early phase), but after 7-10 days they lose this sodium avidity (late phase). Although increased production of a mineralocorticoid, 19-nor-deoxycorticosterone (19-Nor-DOC), has been implicated, 19-Nor-DOC levels during the early and late phases of AE have not been systematically measured. Furthermore it is not known why 19-Nor-DOC production should increase during a time when production of 11 beta- and 18-hydroxylated corticosteroids are decreased in AE. The purpose of this study was to examine the 11 beta, 18-, and 19-hydroxylase pathways in the early and late phases of AE. The results demonstrate increased urinary 19-Nor-DOC and decreased 18-OH-DOC and corticosterone excretion in the early phase of AE at a time when adrenal mitochondrial 11 beta- and 18-hydroxylase activities were decreased but 19-hydroxylase activity was unchanged. During the late phase of AE, urinary 19-Nor-DOC had decreased and 18-OH-DOC and corticosterone had increased to levels indistinguishable from those in sham controls. This reduction in 19-Nor-DOC was associated with a decrease in 19-hydroxylase activity in AE. Since the 11 beta, 18-, and 19-hydroxylases have a common substrate (DOC), it is possible that differential flux of DOC through these pathways could account for the changes in steroid production in AE. These data suggest that the increased 19-Nor-DOC excretion in AE may be due to alterations in enzyme activity leading to a shunting of DOC into the 19-Nor-DOC pathway. In addition, the synchronicity of 19-Nor-DOC with sodium excretion suggests that it has an important role in the pathogenesis of the sodium retention in AE.

Mineralocorticoid activity of 19-nor-corticosterone and 19-nor-progesterone in the toad bladder.

19-Nor-corticosteroids are potentially important mineralocorticoids and hypertensive agents. We tested the mineralocorticoid potency of 19-nor-progesterone (19-NOR-P) and 19-nor-corticosterone (19-NOR-B) compared with aldosterone using the toad bladder short-circuit current as a measure of sodium transport. 19-NOR-B (10(-7) M) increased sodium transport to a degree not different from that caused by aldosterone (10(-7) M). The onset of action and duration of activity also were not different from those of aldosterone. 19-NOR-P (10(-7) M), however, had no effect on sodium transport. We conclude that 19-NOR-B has significant mineralocorticoid activity, while under the conditions of these studies, 19-NOR-P exhibited no effect on sodium transport.

19-Nor-deoxycorticosterone production from aldosterone-producing adenomas.

19-Nor-deoxycorticosterone (19-nor-DOC), a hypertensinogenic mineralocorticoid, equipotent with aldosterone and independent of the renin-angiotensin system, is synthesized in the kidney and excreted in excess in the urine of patients with aldosterone-producing adenomas. This current study evaluated the adrenal and renal venous levels of aldosterone and 19-nor-DOC after adrenal and renal venous catheterization and blood sampling in five patients with aldosterone-producing adenomas. Aldosterone (mean +/- SEM) in the adrenal vein ipsilateral to the tumor (469 +/- 293 ng/dl) was higher than in the contralateral vein (70 +/- 59 ng/dl). 19-Nor-DOC (mean +/- SEM) was also higher in the ipsilateral (548 +/- 286 ng/dl) than in the contralateral (51 +/- 14 ng/dl) adrenal vein. In the renal veins, ipsilateral aldosterone (2.2 +/- 0.8 ng/dl) and 19-nor-DOC (12.2 +/- 2.4 ng/dl) were respectively similar to contralateral aldosterone (1.5 +/- 0.5 ng/dl) and 19-nor-DOC (14.6 +/- 1.3 ng/dl), whereas 19-nor-DOC was higher than aldosterone in each renal vein. The present study demonstrates that 19-nor-DOC is produced, not only from the kidneys, but also from the ipsilateral adrenal of patients with aldosterone-producing adenomas. The ipsilateral adrenal 19-nor-DOC production is comparable to that of aldosterone, suggesting that 19-nor-DOC may be contributing to the hypertension and hypokalemia in this disease. In the contralateral adrenal, aldosterone is suppressed to a greater extent than 19-nor-DOC, suggesting that these two steroids are under the influence of two different regulatory mechanisms.

Hypertensinogenic potencies of aldosterone and deoxycorticosterone in the rat.

Hypertensinogenic potency and other effects of acetate salts of aldosterone (ALA) and deoxycorticosterone (DOCA) were evaluated in 50-day-old mononephrectomized and saline-drinking Sprague-Dawley CD male rats. The steroids were administered by continuous subcutaneous infusion in a dose of 100 microgram/24 hrs by means of Alzet osmotic minipumps implanted subcutaneously. Within 3 weeks of steroid treatment, systolic blood pressure, measured in the tail of conscious animals by a photoelectric cell method at 27 degrees C environmental temperature, increased significantly in ALA rats as compared to that in DOCA rats, which was not different from controls. ALA rats exhibited marked polydipsia, decreased body weight, hypernatremia, hypokalemia, cardiomegaly, and kidney enlargement, whereas DOCA rats exhibited only cardiomegaly when compared with controls. The degree of cardiomegaly in ALA and DOCA rats was statistically much greater than the differences in their respective blood pressure levels when compared to controls. Under the conditions of this study, it is concluded that: 1) the hypertensinogenic potency of ALA is greater than that of DOCA; 2) ALA and DOCA may induce cardiomegaly, independent of their effect on blood pressure; 3) Alzet osmotic minipumps are effective tools for the administration of steroids by continuous infusion.

Prohormones in adrenal venous effluent in patients with primary hyperaldosteronism.

Aldosterone-producing adenoma (APA) and idiopathic hyperplasia (IHA) are two main causes of primary hyperaldosteronism, which differ in the modes of treatment. Some of the prohormones, such as 18-hydroxycorticosterone, are elevated in adenomas. 19-Nor-deoxycorticosterone (19-nor-DOC), produced in the kidney, has been shown to be excreted in excess in patients with APA. Deoxycorticosterone is a known precursor of aldosterone and 19-nor-DOC. This study is designed to evaluate the levels of prohormones in adrenal venous effluent in eight patients, three with APA, of which two were confirmed by surgical pathology and four with IHA, and one patient with primary adrenal hyperplasia. 19-OH-DOC, a precursor of 19-nor-DOC, was found to be the main prohormone in adrenal venous effluent in patients with both APA and IHA. 19-Oic-deoxycorticosterone and 19-nor-DOC were also detected, but in smaller quantities. 19-OH-DOC appears to be the main prohormone in adrenal venous effluent for the biosynthesis of 19-nor-DOC.

Treatment of Cushing's syndrome with trilostane (WIN 24,540), an inhibitor of adrenal steroid biosynthesis.

Seven patients with Cushing's syndrome were treated with trilostane (WIN 24,540) 4 alpha,5-epoxy-17 beta-hydroxy-3-oxo-5 alpha-androstane-2 alpha-carbonitrile), an inhibitor of adrenal steroid biosynthesis. Trilostane treatment reduced steroid biosynthesis and it also improved biochemical manifestations of the disease in all of the patients treated. The average cortisol secretory rate decreased significantly with treatment, from 47.1 to 23.4 mg/24 h (P less than 0.005), and urinary 17-hydroxycorticosteroids decreased from 15.7 to 8.7 mg/24 h (P less than 0.01). Urinary free cortisol excretion decreased from 277 to 88 microgram/24 h (P less than 0.01), and 0800 h plasma cortisol levels declined from 25.0 to 12.0 microgram/dl (P less than 0.05). Conversely, dehydroepiandrosterone sulfate excretion in urine increased from 1.3 to 5.8 mg/24 h (P less than 0.0025) and in plasma increased from 162 mg/24 h (P less than 0.025). Plasma and urinary free dehydroepiandrosterone increased 2-fold. Urinary 17-ketosteroid excretion increased from 18 to 43 mg/24 h (P less than 0.001). A significant reduction in urinary excretion of tetrahydroaldosterone, tetrahydrodeoxycorticosterone, and 18-hydroxytetrahydrodeoxycorticosterone was observed with treatment. Inhibition of steroid biosynthesis was accompanied by a 2-fold increase in PRA and no change in serum cholesterol levels. Mean arterial blood pressure decreased with treatment from 109 to 97 mm Hg (P less than 0.005), and fasting blood sugar decreased from 117 to 98 mg/dl (P less than 0.005), accompanied by rise in plasma potassium levels from 3.8 to 4.3 milliequivalents/liter (P less than 0.025). Two patients on long term therapy also showed an improvement in clinical features of their disease. There were no significant treatment-related carcinoma, simultaneously producing both an excessive amount of cortisol and ACTH, is described. It is concluded that trilostane is an effective inhibitor of 3 beta-hydroxysteroid dehydrogenase enzyme system in human adrenal gland; it inhibits biosynthesis of cortisol and it is useful in the treatment of Cushing's syndrome.

Antihypertensive effects of an aromatase inhibitor in inbred salt-sensitive rats.

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess urinary 19-nordeoxycorticosterone compared with salt-resistant control rats (SR/Jr). 19-Nordeoxycorticosterone is a hypertensinogenic mineralocorticoid, but whether it contributes to the salt sensitivity of SS/Jr is unknown. This study sought to evaluate the contribution of 19-nordeoxycorticosterone to the salt sensitivity of SS/Jr by lowering its production with an aromatase inhibitor, 10-propargyl-androst-4-ene,3,17-dione (19-acetylenic-androstenedione, 19-AA). This aromatase inhibitor also preferentially inhibits nonaromatizing adrenal 19-hydroxylation, an essential step in the formation of 19-nordeoxycorticosterone. To test this hypothesis, inhibitor (120 mg) or vehicle pellets were implanted into male and female weanling SS/Jr at 42 days of age. A high salt diet (8% NaCl) was started and two additional pellets were implanted at 52 and 62 days of age. Systolic blood pressure was measured in all animals and urinary corticosteroids in males. Compared with vehicle, the inhibitor lowered blood pressure at 50 days of age (when it could first be measured) until 64 days of age in females and 71 days of age in males. Corticosterone and aldosterone levels were not different between 19-AA- and vehicle-treated SS/Jr. 19-Nordeoxycorticosterone levels, however, were mildly reduced with the inhibitor (0.05 less than p less than 0.10). After 28 days of high salt diet all 23 of the 19-AA-treated SS/Jr were alive, whereas almost one half of the control animals had died. These data demonstrate that 19-AA attenuates the hypertension in SS/Jr; this effect may be through reduction in 19-nordeoxycorticosterone production.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effects of an aromatase inhibitor in the spontaneously hypertensive rat.

Recent studies from this laboratory have demonstrated that 19-nor-deoxycorticosterone, a potent mineralocorticoid, has been excreted in excess in the urine of young spontaneously hypertensive rats (SHR). Although urinary 19-nor-deoxycorticosterone levels decline before the onset of hypertension, preliminary evidence suggests that 19-nor-deoxycorticosterone is further oxygenated to other steroid products in older SHR. Since 19-hydroxylation is the essential first step in the formation of 19-nor-deoxycorticosterone from deoxycorticosterone and since the mechanism-based aromatase inhibitor 10-propargyl-androst-4-ene,3,17-dione preferentially inhibits 19-hydroxylation, this agent was administered to weanling SHR to determine whether inhibition of 19-nor-deoxycorticosterone formation could modify or prevent hypertension. Accordingly, either 10 mg of 10-propargyl-androst-4-ene,3,17-dione or vehicle (control) was injected daily for several weeks in 4.5 week-old SHR. Injection of 10-propargyl-androst-4-ene,3,17-dione reduced urinary free 19-nor-deoxycorticosterone and retarded the development of hypertension compared with the effect of vehicle injection (p less than 0.05). Mean blood pressure levels in SHR receiving 10-propargyl-androst-4-ene,3,17-dione were lower than those in SHR receiving vehicle for each of the first 8 weeks of treatment (p less than 0.05). These data support the importance of 10-nor-corticosteroids in the pathogenesis of hypertension in SHR.

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.

Converting-enzyme inhibitor administration lowers urinary free 19-nor-deoxycorticosterone levels.

19-Nor-deoxycorticosterone (19-nor-DOC) is a human mineralocorticoid. The regulation of its secretion is poorly understood, as renin angiotensin II (ANG II) stimulation has minimal effects on 19-nor-DOC. This study sought to determine if ANG II inhibition would decrease 19-nor-DOC production. Six normal subjects on fixed electrolyte intake were admitted to a metabolic unit. After a 5-day control period to establish electrolyte balance, enalapril, p.o., 10 mg/day, was administered for 28 days. This treatment resulted in ANG II inhibition, which was reflected by a rise in plasma renin activity, a blunting of the postural plasma aldosterone increment, and a decrease in aldosterone secretion rate (ASR). Levels of urinary free (UF) 19-nor-DOC progressively decreased from 294 +/- 108 ng/day on Day 0 to 164 +/- 70 on Day 3, 141 +/- 62 on Day 7, 101 +/- 38 on Day 14, 68 +/- 18 on Day 21, and 106 +/- 31 on Day 28. The decrease in 19-nor-DOC levels was synchronous with the fall in ASR (R = 0.94, n = 5, p less than 0.005), but it was of greater magnitude (71% decrease in 19-nor-DOC levels versus 41% decrease in ASR). In addition, the decrease in 19-nor-DOC levels correlated with a fall in urinary potassium and an increase in both urinary sodium and chloride (R = 0.68, -0.79, -0.87 respectively; n = 6, p less than 0.05). The fall in ASR, on the other hand, was not significantly correlated with the changes in these urinary electrolyte levels (R = 0.65, 0.64, 0.57 respectively; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)