19-nordeoxycorticosterone and Hypertension

Topics: Aldosterone; Androstenedione; Animals; Desoxycorticosterone; Female; Humans; Hypertension; Pregnancy; Rats

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess 19-nor-deoxycorticosterone (19-nor-DOC) compared with salt-resistant control rats (SR/Jr). 19-Nor-deoxycorticosterone is a hypertensinogenic mineralocorticoid believed to contribute to the salt sensitivity of SS/Jr. 19-Acetylenic-deoxycorticosterone (19-Ac-DOC), an inhibitor of 19-nor-DOC biosynthesis, was evaluated for its antihypertensive effect in 20 hypertensive female SS/Jr rats. At 60 days of age, the rats were started on a high-salt diet (8% NaCl); then, at 120 days, the 10 surviving rats were divided into two groups. Group 1 included five animals with blood pressure +/- standard error (BP +/- SE) of 208 +/- 2 mm Hg that had 19-Ac-DOC implants (1 mg released over 10 days). Group 2 consisted of five animals with a BP of 204 +/- 2 mm Hg that had placebo implants (vehicle only). At 130 days, when another set of pellets was implanted, four rats were still alive in group 1 (BP 165 +/- 5 mm Hg) and none in group 2. At 140 days, the four surviving rats had a BP of 157 +/- 2 mm Hg. Finally, at 150 days, after 10 days off any 19-Ac-DOC, only two rats remained alive (BP 200 +/- 0 mm Hg). Urinary corticosterone +/- SE, DOC +/- SE, and 19-nor-DOC +/- SE before the first implant were 10 +/- 3, 16 +/- 5, and 42 +/- 14 micrograms/week, respectively, and 7 +/- 2, 13 +/- 5, 23 +/- 13 micrograms/week, respectively, after the second implant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Desoxycorticosterone; Diet; Drug Implants; Drug Resistance; Female; Hypertension; Rats; Rats, Mutant Strains; Sodium Chloride; Survival Analysis

Two strains of spontaneously hypertensive rats (SHRs) differ in their susceptibility to the hypertensive effects of dietary NaCl. One strain exhibits a significant elevation of blood pressure after dietary NaCl loading (SHR-S), whereas the other does not (SHR-R). Since differences in adrenocortical steroid production may contribute to NaCl sensitivity, we compared 19-nordeoxycorticosterone (DOC), 18-OH-DOC, aldosterone, and corticosterone excretion in 6-week-old male rats from the SHR-S (n = 24) and SHR-R (n = 24) strains. The rats were housed in metabolic cages (two rats per cage) and given either basal (1%) or high (8%) NaCl diet. Urinary steroids were analyzed using thin-layer chromatography and radioimmunoassay methods. The high NaCl diet elevated the urinary excretion of the four corticosteroids in both rat strains. 19-nor-DOC decreased with time in both the SHR-S and SHR-R strains, and was not different between strains on either diet. Aldosterone was increased in the SHR-S strain compared with the SHR-R strain on the low NaCl diet, but aldosterone was not different between the two strains on the high NaCl diet. Corticosterone and 18-OH-DOC did not differ between strains. These data confirm that 19-nor-DOC is higher in young prehypertensive SHRs and decreases with age. Aldosterone excretion is higher in the SHR-S strain compared with the SHR-R strain on the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Animals; Blood Pressure; Chromatography, Thin Layer; Corticosterone; Desoxycorticosterone; Hydroxycorticosteroids; Hypertension; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Sodium, Dietary

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess 18-hydroxydeoxycorticosterone (18-OH-DOC) and 19-nor-DOC compared to control rats (SR/Jr). This may be caused by an abnormal adrenal 11 beta-hydroxylase, which catalyzes the 11 beta, 18, and 19-hydroxylations of DOC. A comparison of the urinary products of this enzyme including 18-OH-DOC, 19-nor-DOC, corticosterone (B), and 18-OH-B have not been described in the SS/Jr. Therefore, these steroid products were measured at 7 and 12 weeks of age in 36 weanling male and female, SS/Jr and SR/Jr (n = 9 in each group), on a low-salt diet. In both the male and female SS/Jr urinary free levels of 18-OH-DOC, 19-nor-DOC, and 18-OH-B were elevated, while B was not different at 6 and 10 weeks of age. The largest increases were in 18-OH-B levels, and these levels correlated with 18-OH-DOC and B but not 19-nor-DOC. The high degree of correlation between these steroids probably reflects their closely related dependence on adrenal 11 beta-hydroxylase biosynthesis.

Topics: 18-Hydroxycorticosterone; Adrenal Glands; Animals; Desoxycorticosterone; Drug Resistance; Female; Hypertension; Male; Rats; Rats, Inbred Strains; Sodium Chloride; Steroid 11-beta-Hydroxylase

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)

Topics: Aldosterone; Androstenedione; Animals; Antihypertensive Agents; Aromatase Inhibitors; Cortisone; Desoxycorticosterone; Female; Hypertension; Male; Pargyline; Rats; Rats, Inbred Strains; Sodium Chloride

Adrenal cysts are rare, but they have been disproportionately associated with hypertension. This report describes a hypertensive patient with increased levels of 19-nor-deoxycorticosterone (19-nor-DOC), a potent mineralocorticoid. The patient was a thirty year old man with hypokalemia, moderately severe hypertension, suppressed PRA, and low aldosterone secretion. Following surgical removal of a 10 cm adrenal cyst, the hypertension improved, the hypokalemia resolved, and the PRA and the aldosterone secretion normalized. Urinary 19-nor-DOC pre-op was elevated 4.6 microgram per day (normal less than 1.0 microgram/day and subsequently became normal at 0.7 microgram per day following surgery. The adrenal cyst was a fibrous walled structure containing mucinous straw-colored fluid. Pericystic adrenocortical tissue demonstrated increased 19-OH-DOC production (a 19-nor-DOC precursor) which may have been responsible for the 19-nor-DOC excess. We hypothesize that compressive adrenal damage from the cyst may produce a form of adrenal regeneration hypertension which is known to be associated with 19-nor-DOC excess.

Topics: Adrenal Gland Diseases; Adult; Blood Pressure; Cysts; Desoxycorticosterone; Humans; Hypertension; Male; Mineralocorticoids; Renin

19-Nor-deoxycorticosterone is a newly recognized mineralocorticoid which has been associated with some forms of genetic, experimental, and human hypertension. To further examine this relationship, specific inhibitors of 19-nor-deoxycorticosterone biosynthesis must be developed. Since 19-hydroxylation is the pivotal step in both 19-nor-deoxycorticosterone biosynthesis and aromatization of androgens to estrogens, we evaluated an aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione on the inhibition of 19-hydroxylation in both rat and human adrenal mitochondria in vitro and 19-nor-deoxycorticosterone production and blood pressure in spontaneously hypertensive rats in vivo. Adrenal mitochondria from 48 male Sprague-Dawley rats and 1 patient with an aldosterone-producing adenoma were incubated in the presence of deoxycorticosterone substrate both with and without 4-hydroxyandrost-4-ene-3,17-dione. 4-Hydroxyandrost-4-ene-3,17-dione produced significant inhibition of 19-hydroxy-deoxycorticosterone production in both rat and human adrenal mitochondria, with a smaller and not significant inhibition of corticosterone and 18-hydroxy-corticosterone. 4-Hydroxyandrost-4-ene-3,17-dione given subcutaneously to spontaneously hypertensive rats lowered 19-nor-deoxycorticosterone by 69% and completely abolished hypertension compared to Wistar-Kyoto controls. These data demonstrate that 4-hydroxyandrost-4-ene-3,17-dione is a specific inhibitor of 19-hydroxylase, that it lowers 19-nor-deoxycorticosterone production and prevents hypertension in the spontaneously hypertensive rat. These studies reinforce the possible pathogenic significance of 19-nor-deoxycorticosterone in hypertension in spontaneously hypertensive rats.

Topics: Androstenedione; Animals; Desoxycorticosterone; Humans; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

Rats were selectively bred for susceptibility (S) and resistance (R) to the hypertensinogenic effects of excess salt intake by Dahl and further inbred to virtual homozygosity by Rapp (S/JR and R/JR). The S strain has been shown to have a mutation of the cytochrome P-450-dependent 11 beta,18-hydroxylase resulting in the enhanced production of 18-hydroxydeoxycorticosterone (18-OH-DOC) compared to that of the R strain. It is known that this enzyme is also responsible for the hydroxylation of deoxycorticosterone at the 19 position to produce 19-hydroxydeoxycorticosterone. Recently, the excretion of 19-nordeoxycorticosterone (19-nor-DOC), a potent mineralocorticoid, has been shown to be markedly increased in S/JR females compared to that in R/JR females consuming a high sodium diet. While the S/JR rat is spontaneously hypertensive, the course of the disease is greatly accelerated and exacerbated by a high sodium diet. If, indeed, 19-nor-DOC is responsible for the spontaneous hypertension in the S/JR rat, then its production should also be higher in the S/JR rat consuming a normal salt diet. Furthermore, since its production is suppressed by NaCl intake, the excretion should be even higher when not suppressed by a high sodium diet. We measured the urinary excretion of 19-nor-DOC, 18-OH-DOC, and corticosterone in male and female S/JR and R/JR rats consuming a normal sodium diet. The excretions of corticosterone and 18-OH-DOC were significantly higher by S/JR of both sexes than by R/JR, with the excretion by female rats being higher than that by male rats within the same strain. The hierarchy of excretion rates of 19-nor-DOC was: S/JR females greater than R/JR females greater than S/JR males greater than R/JR male rats. These studies indicate that while S/JR rats of both sexes develop higher blood pressures than the R/JR even on a standard salt intake, the excretion of 19-nor-DOC does not correlate well with their blood pressure elevation, since the normotensive female R/JR rat excretes significantly higher quantities of 19-nor-DOC than the hypertensive male S/JR rat. Thus, it is unclear whether 19-nor-DOC is playing a significant role in the pathogenesis of the hypertension in the S/JR rat. It also remains unknown whether the renal site of formation of 19-nor-DOC allows access to the mineralocorticoid target sites in the kidney.

Topics: Animals; Blood Pressure; Corticosterone; Desoxycorticosterone; Female; Hypertension; Male; Rats; Rats, Inbred SHR; Sex Characteristics; Sodium, Dietary

Normal pregnancy and pre-eclampsia are associated with water and sodium retention. Therefore various mineralocorticoids have been evaluated in normal and abnormal pregnancies. This study reports the urinary free 19-nor-deoxycorticosterone (19-nor-DOC) and deoxycorticosterone (DOC) levels in normal pregnancy and in patients with pregnancy-induced hypertension. Levels of 19-nor-DOC and DOC were not significantly different between normal patients in the third trimester and women with pregnancy-induced hypertension at a comparable gestational age. The urinary excretion of 19-nor-DOC in pregnancy was noted to be significantly lower than that previously reported in normal male volunteers. There was a positive correlation between 19-nor-DOC excretion and increasing gestational age. These data are compatible with the view that 19-nor-DOC may not play a role in pregnancy-induced hypertension. However, a larger study of primigravid women, with and without, pre-eclampsia is needed to confirm this finding.

Topics: Adult; Desoxycorticosterone; Eclampsia; Female; Gestational Age; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular

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.

Topics: Aging; Androstenedione; Animals; Blood Pressure; Desoxycorticosterone; Hypertension; Male; Pargyline; Rats; Rats, Inbred SHR

The urinary excretion of deoxycorticosterone (DOC) and 19-nor-deoxycorticosterone (19-nor-DOC) was measured using a technique which consisted of the purification of both steroids by high pressure liquid chromatography followed by RIA using specific antibodies. The urinary excretion of DOC was 29.4 +/- 25 ng/24 h (mean +/- SD) in 35 normal subjects, 26 +/- 21 ng/24 h in 46 patients with low renin hypertension (LRHT), and 32 +/- 23 ng/24 h in 16 patients with normal renin hypertension (NRHT). The urinary excretion of 19-nor-DOC was 287 +/- 178 ng/24 h in normal subjects, 224 +/- 167 ng/24 h in LRHT patients, and 235 +/- 170 ng/24 h in NRHT patients. There were no hypertensive patients with increased excretion of 19-nor-DOC. The excretion of 19-nor-DOC increased after 3 days of sodium depletion in normal and hypertensive subjects, but the increment was significantly higher in normotensive subjects. There was no correlation between the excretion of 19-nor-DOC and that of DOC or urinary aldosterone. This study suggests that DOC or 19-nor-DOC does not play a role in the pathogenesis of either LRHT or NRHT and disagrees with previous reports suggesting such a role.

Topics: Adult; Aged; Aldosterone; Desoxycorticosterone; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Renin

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.

Topics: Animals; Desoxycorticosterone; Diet, Sodium-Restricted; Disease Susceptibility; Female; Hypertension; Immunity, Innate; Male; Rats; Sodium Chloride

19-Nor-deoxycorticosterone (19-nor-DOC) is a naturally occurring, potent mineralocorticoid present in hypertensive animal models as well as man. To investigate 19-nor-DOC's regulation and possible pathogenesis in hypertension, urinary free (UF) 19-nor-DOC was measured in 14 hypertensives, correlated with other corticosteroids and systemic arterial blood pressure (BP), and compared to basal and ACTH-stimulated values in 8 normotensive subjects. Seven of the 14 hypertensives had low-renin hypertension, 2 had primary aldosteronism, 1 had an adrenal carcinoma, and another had acromegaly. These studies determined that: 1) although the mean UF 19-nor-DOC was not increased in hypertensives (588 +/- 180 vs. 428 +/- 122 ng/day), 2 low-renin hypertensives had quite elevated levels (2186 and 2018); 2) the UF 19-nor-DOC in hypertensives was correlated with BP but not with PRA, aldosterone secretion, plasma potassium, basal plasma cortisol, or 17-hydroxycorticosteroids; 3) likewise, in normotensives, UF 19-nor-DOC did not correlate with basal plasma cortisol, cortisol secretion, or 17-hydroxycorticosteroids excretion but did correlate after ACTH stimulation. Therefore, although 19-nor-DOC is activated by ACTH administration, it is not correlated with basal parameters of cortisol production, suggesting that factors other than ACTH regulate basal 19-nor-DOC secretion. Furthermore 19-nor-DOC is elevated in some hypertensive patients, and it is directly related to the elevation of mean systemic BP. This suggests that, although 19-nor-DOC could contribute to hypertensive disease in some individuals, it does not appear to be due to excess ACTH.

Topics: 17-Hydroxycorticosteroids; Acromegaly; Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Adult; Aged; Blood Pressure; Desoxycorticosterone; Female; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Male; Middle Aged; Pituitary Neoplasms; Renin

Nonaldosterone mineralocorticoids, such as deoxycorticosterone (DOC) and 18-hydroxy-DOC, have been reported to be elevated in some patients with primary aldosteronism (PA). Since DOC is a probable precursor of a more potent mineralocorticoid, 19-nor-deoxycorticosterone (19-nor-DOC), this study evaluated urinary free (UF) 19-nor-DOC excretion in 6 patients with PA and compared the results to those from 11 patients with low renin hypertension (LRH) and 7 normotensive subjects. PA was due to either an aldosterone-producing adenoma (APA; 4 patients) or bilateral adrenal hyperplasia (2 patients) diagnosed by adrenal venous catheterization or surgery. Compared to LRH subjects, patients with PA had a higher mean blood pressure (137 +/- 9 vs. 114 +/- 3 mm Hg), a lower plasma potassium level (3.1 +/- 0.2 vs. 3.9 +/- 0.1 meq/1) and greater renin suppression (0.3 +/- 0.1 vs. 0.6 +/- 0.1 ng angiotensin I/ml . h). UF 19-nor-DOC levels were elevated in PA subjects compared to those in normotensives (3,716 +/- 1,517 vs. 428 +/- 112 ng/day) but not compared to those in LRH patients (1,237 +/- 471). Two patients with APA had distinctly elevated UF 19-nor-DOC levels (11,137 and 7,744 ng/day), but another APA patient had the lowest value (305 ng/day). UF 19-nor-DOC positively correlated with the aldosterone secretion rate in PA (r = 0.75) but not LRH subjects. In conclusion, this study demonstrates that patients with PA may have elevated levels of UF 19-nor-DOC which are proportional to the aldosterone excess and could be a contributing factor to the hypertension, hypokalamia, and excess mineralocorticoid activity of this disease.

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenal Glands; Adult; Aged; Aldosterone; Desoxycorticosterone; Female; Humans; Hyperaldosteronism; Hyperplasia; Hypertension; Kinetics; Male; Middle Aged; Renin

An enzyme immunoassay of 19-nor-deoxycorticosterone in rat serum was established. The normal value of 19-nor-DOC in rat serum obtained from 9:00 am to 10:00 am was 148 +/- 30 ng/dl (mean +/- SE,n = 10). Serum levels of this steroid decreased in rats with adrenal regeneration hypertension during the course of the experiment up to 8 weeks, while systolic blood pressure rose progressively. We concluded that this mineralocorticoid is not involved at least as a circulating hormone in the pathogenesis of adrenal regeneration hypertension in rats.

Topics: Adrenal Glands; Animals; Blood Pressure; Desoxycorticosterone; Hypertension; Kinetics; Male; Rats; Rats, Inbred Strains; Regeneration; Time Factors

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Aldosterone; Blood Pressure; Desoxycorticosterone; Humans; Hypertension; Mineralocorticoids; Renin; Sodium

Topics: Age Factors; Animals; Desoxycorticosterone; Female; Hypertension; Male; Rats; Rats, Inbred Strains; Sex Factors

Topics: Adrenocorticotropic Hormone; Adult; Aldosterone; Desoxycorticosterone; Electrolytes; Female; Humans; Hydrocortisone; Hypertension; Male; Renin