19-Nor-Deoxycorticosterone: A Potent Mineralcocorticoid Isolated from the Urine of Rats with Regenerating Adrenals*

SUMMARY To support our contention that the Wistar-Furth rat is resistant to mineralocorticoid hypertension, we assessed the effects of deoxycorticosterone (DOC) administration or renal artery stenosis on the development of hypertension in the Sprague-Dawley and Wistar-Furth rat strains. Weekly administration of mineralocorticoid in the form of DOC pivalate resulted in rapid, severe hypertensive cardiovascular disease in Sprague-Dawley rats. Within 5 weeks the mean conscious systolic blood pressures in steroid-treated and control rats were 186 ± 4 and 118 ± 5 mm Hg, respectively. In contrast, blood pressures of Wistar-Furth rats were only moderately elevated, even after 10 weeks of DOC pivalate administration (136 ± 2 vs 116 ± 2 mm Hg for controls). Furthermore, none of the steroid-treated Wistar-Furth animals exhibited cardiovascular lesions. In parallel studies, littermates of these rat strains were subjected to renal artery stenosis and blood pressures were determined weekly in conscious rats. Silver clip constriction of the left renal artery, in the presence of the contralateral kidney, resulted in a rapid, sustained elevation of blood pressure in both SpragueDawley and Wistar-Furth rat strains (177 ± 4 and 176 ± 5 mm Hg, respectively). Corticosteroid levels were also determined in DOC-treated Sprague-Dawley and Wistar-Furth rats. The regimen employed resulted in a 10-fold increase in DOC levels as compared with controls, and the levels achieved were comparable in both strains. Thus, the Wistar-Furth rat appears to be selectively resistant to mineralocorticoid hypertensive vascular disease and thus affords a model for studying mechanisms of steroid hypertension. (Hypertension 10: 176-180, 1987) KEY WORDS • hypertension • deoxycorticosterone • resistance • Wistar-Furth rats W E have previously reported that adrenal regeneration hypertension fails to develop in the Wistar-Furth rat strain. 1 WistarFurth rats (W/Fu) do exhibit cardiac and renal hypertrophy, but systolic blood pressure (BP) is minimally elevated and there is a virtual absence of cardiovascular lesions. This model of experimental hypertension was described by Skelton 2 in 1955 and is generally thought to be mediated by mineralocorticoid excess. 3 The identity of the hormone (or hormones) involved has not been clearly defined, although several steroids, including 11-deoxycorticosterone (DOC) and 19-nordeoxycorticosterone have been implicated. 4 ation as compared with those of controls. Again, BP was mildly elevated but cardiovascular lesions were absent. This study and our previous one 1 suggested the possibility that the W/Fu are resistant to mineralocorticoid hypertension. In contrast to our observations, Hall et al. 9 reported that W/Fu exhibit adrenal regeneration hypertension that is indistinguishable from that seen in SpragueDawley rats (SD). However, in a follow-up study, the same authors found that adrenal regeneration hypertension developed in SD at a much faster rate and with greater intensity than in the W/Fu. 10 In fact, BPs of the ...

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confidence: 99%

Resistance to mineralocorticoid-induced hypertensive vascular disease.

Sciotti¹,

Gallant²

1987

“…The radioimmunoassay for 19-nor-DOC has been previously described. 3 Dr. Celso Gomez-Sanchez graciously provided the antibody and The nonspecific binding without antibody was 2.5%, nearly identical to the nonspecific binding when excess 19-nor-DOC was added (800 pg, 2.3%; 2000 pg, 2.4%; 4000 pg, 2.2%; 10,000 pg, 2.2%). The specificity of the 19-nor-DOC antibody for other corticosteroids is shown in Table 2.…”

Section: Methodsmentioning

confidence: 81%

“…The biological significance of 19-nor-DOC was elucidated by the studies of Gomez-Sanchez et al 3 in rat adrenal regeneration hypertension. As 19-nor-DOC is a potent mineralocorticoid produced by both humans and rats, 4 -7 it would be of considerable interest to define the production and metabolism of this hormone in normal and hypertensive subjects.…”

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confidence: 99%

Unconjugated and conjugated urinary 19-nor-deoxycorticosterone glucosiduronate. Elevated levels in essential hypertension.

Griffing¹,

Wilson²,

Melby³

1985

SUMMARY The mlneralcorticoid 19-nor-deoxycorticosterone (19-nor-DOC) is present in the urine of rats and humans in unconjugated and conjugated forms. This study sought to compare levels of unconjugated and conjugated 19-nor-DOC glucosiduronate in essential hypertensive subjects. The essential hypertensive and normal subjects were admitted to a metabolic unit, and plasma and urine were collected at fixed intervals on a fixed-electrolyte intake (Na + , 128 mEq/day, K + , 80 mEq/day). The 19-nor-DOC was purified by chromatography and measured by radioimmunoassay. Unconjugated urinary 19-nor-DOC was elevated in essential hypertensive subjects (195 ± 21 [SE] ng/day; n = 21) compared with levels in normal subjects (118 ± 30 [SE] ng/day; n = 13, p < 0.05). Two essential hypertensive subjects had very high levels (673, 729 ng/day), while levels in seven essential hypertensive subjects were below 118 ng/day. Conjugated 19-nor-DOC glucosiduronate also was elevated in essential hypertensive subjects (950 ± 88 [SE] ng/day; n = 8) compared with levels in normal subjects (680 ± 90 [SE] ng/day; n = 5). Seven of eight essential hypertensive subjects had levels greater than 680 ng/day. The unconjugated and conjugated urinary 19-nor-DOC glucosiduronate levels were positively correlated in both of these groups (rho = 0.82, p < 0.01). Other test results including plasma renin activity, plasma aldosterone levels, aldosterone secretion rates, and plasma and urine electrolyte levels were not different between groups. These results indicate that essential hypertensive subjects have increased 19-nor-DOC excretion, which is reflected by increases in both unconjugated and conjugated glucosiduronate forms. Some essential hypertensive subjects, however, had normal urinary 19-nor-DOC levels, which may reflect the heterogeneity of this disease. sterone (19-nor-DOC) was synthesized more than 40 years ago, 1 and Kagawa and Van Arman 2 subsequently found the sodium-retaining activity of this hormone to be between two and five times that of deoxycorticosterone (DOC) itself. The biological significance of 19-nor-DOC was elucidated by the studies of in rat adrenal regeneration hypertension. As 19-nor-DOC is a potent mineralocorticoid produced by both humans and rats, 4 -7 itFrom the Section

“…The areas corresponding to DOC and 19-nor-DOC were used for radioimmunoassay determinations using relatively specific antibodies previously described. 10 ' l3 The average recovery of (1,2 3 H) DOC and (1,2 3 H) 19-nor-DOC from the whole procedure was 53% ± 4% and 50.7% ± 4.9% respectively. Intraassay variability was 9.8% and 10%, and interassay variability was 19% and 16.6%, for DOC and 19-nor-DOC respectively.…”

Section: Assay Methodsmentioning

confidence: 93%

“…We have identified a powerful mineralocorticoid, 19-nor-deoxycorticosterone (19-nor-DOC), in the urine of rats with ARH 10 and have recently developed a method to measure the urinary excretion of 19-nor-DOC in rats. We are reporting our results of the measurements of free 19-nor-DOC and DOC in the urine and 19-nor-DOC in the serum of rats with adrenal regeneration hypertension.…”

Section: Hypertension • Mineralocorticoidsmentioning

confidence: 99%

Urinary free and serum 19-nor-deoxycorticosterone in adrenal regeneration hypertension.

Gómez-Sánchez¹,

Gómez-Sánchez²,

Upcavage³

et al. 1983

SUMMARY Adrenal regeneration hypertension (ARH) is caused by increased secretion of mineralocorticoids. Deoxycorticosterone (DOC), which has been found in increased concentrations in the blood of rats with ARH after the second week, must play an important role in the pathogenesis of ARH. However, the increased sodium reabsorption early in the regeneration suggests that another steroid might also play a role in ARH. We previously isolated 19-nor-deoxycorticosterone (19-nor-DOC), a mineralocorticoid with two to five times the potency of DOC, from the urine of rats with regenerating adrenals. In this study, ARH was produced, and the urinary excretions of free DOC and 19-nor-DOC and serum 19-nor-DOC were measured on the 23rd day of regeneration, when the systolic blood pressure of the ARH rats was 172 ± 5 mm Hg (SEM, n = 12) in comparison to 129 ± 4 mm Hg for the controls. Urine excretion of 19-nor-DOC was increased from 0.9 ± 0 . 1 ng/day in controls to 2.3 ± 0.6 ng/day in ARH for DOC and from 5.0 ± 1.1 ng/day in controls to 7.9 ± 1.4 ng/ day in ARH for 19-nor-DOC. Serum 19-nor-DOC was undetectable in both groups. These studies suggest that increased DOC might play an important role in ARH by serving as the initial substrate for the formation of a more powerful mineralocorticoid, 19-nor-DOC, as well as by its own mineralocorticoid activity. However, for 19-nor-DOC to be important it would have to be formed from a precursor at the target organ, since it does not seem to be a circulating steroid. scribed by Skelton, 1 is believed to be due to excessive secretion of a mineralocorticoid that occurs as a consequence of adrenal disruption and subsequent regeneration. Most known mineralocorticoids have been measured and found to be either normal or below normal.2 One exception is DOC, which investigators have described as elevated in the plasma, • w even though DOC production is low in the adrenal incubates from ARH animals at the same stage. 4 6 The acceptance that DOC is the sole causative factor for ARH has not been uniform. Hall and Hall 7 have proposed that the inconsistent finding of saline poly-, dipsia argues against DOC being the cause of ARH. In addition, during the first week of ARH when DOC production and plasma concentrations are low, 3 there is evidence of a salt-retaining factor of adrenal origin 8 ' 9 of unknown identity. hypertension • mineralocorticoidsWe have identified a powerful mineralocorticoid, 19-nor-deoxycorticosterone (19-nor-DOC), in the urine of rats with ARH 10 and have recently developed a method to measure the urinary excretion of 19-nor-DOC in rats. We are reporting our results of the measurements of free 19-nor-DOC and DOC in the urine and 19-nor-DOC in the serum of rats with adrenal regeneration hypertension.