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(Hypertension. 1996;27:197-201.)
© 1996 American Heart Association, Inc.

Articles

Endogenous Renal 11ß-Hydroxysteroid Dehydrogenase Inhibitory Factors in Patients With Low-Renin Essential Hypertension

Yoshiyu Takeda; Isamu Miyamori; Kazuhiro Iki; Satoru Inaba; Kenji Furukawa; Haruhiko Hatakeyama; Takashi Yoneda; Ryoyu Takeda

From the Second Department of Internal Medicine (Y.T., I.M., K.I., S.I., K.F., H.H., T.Y., R.T.) and Department of Health Sciences (Y.T.), School of Medicine, Kanazawa (Japan) University.

Correspondence to Yoshiyu Takeda, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan.

	Abstract

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Abstract 11ß-Hydroxysteroid dehydrogenase (11ß-HSD) modulates the access of corticosteroids to their receptors and is important in blood pressure control. The excretion of renal 11ß-HSD (ie, NAD⁺-dependent isoform) is thought to protect renal mineralocorticoid receptors from cortisol. To examine whether endogenous renal 11ß-HSD inhibitory factor(s) may be involved in the pathophysiology of hypertension, we studied the urinary excretion of such inhibitors in 30 patients with low-renin essential hypertension and 20 normotensive control subjects. The effect of sodium restriction on the urinary excretion of the inhibitors was also evaluated in six normotensive control subjects. Urine was extracted with Sep-Pak cartridges and high-performance liquid chromatography. Endogenous renal 11ß-HSD inhibitors were measured by the inhibition of 11ß-HSD bioactivity in microsomes from the human kidney. The urinary excretion of the inhibitors was significantly increased in patients with low-renin essential hypertension (1280±88 nmol/d, mean±SEM) compared with normotensive control subjects (704±56 nmol/d) (P<.05). Ratios of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone did not differ significantly. Sodium restriction reduced the urinary excretion of the endogenous renal 11ß-HSD inhibitors but did not affect the ratio of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone. Endogenous renal 11ß-HSD inhibitory factors may contribute to the pathogenesis of low-renin essential hypertension by modulating the activity of 11ß-HSD. Sodium intake may directly or indirectly regulate the inhibitory factors.

Key Words: hydroxysteroid dehydrogenase • adrenal cortex hormones • renin • kidney

	Introduction

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The enzyme 11ß-HSD catalyzes the conversion of glucocorticoids to their inactive metabolites.¹ A deficiency of 11ß-HSD, whether congenital² or produced by inhibition of this enzyme related to the administration of licorice³ or carbenoxolone,⁴ leads to the activation of mineralocorticoid receptors by glucocorticoids, resulting in sodium retention and hypertension. A decreased activity of 11ß-HSD has been demonstrated in some essential hypertensive patients⁵ and genetically hypertensive rats.^{6 7}

Biochemical studies have revealed the existence of two isoforms of 11ß-HSD, NAD⁺ dependent and NADP⁺ dependent.⁸ In 1992, Morris et al⁹ reported the excretion of the endogenous inhibitors of 11ß-HSD in human urine. They referred to these inhibitors as GALFs. Walker et al^{10 11} reported these endogenous hepatic 11ß-HSD inhibitors (ie, NADP⁺-dependent) to be unlikely contributors to the pathogenesis of hypertension. The renal 11ß-HSD (ie, NAD⁺-dependent isoform) is thought to be responsible for protecting the renal mineralocorticoid receptors from cortisol.¹²

A possible mechanism of low-renin hypertension is volume expansion with or without mineralocorticoid excess.¹³ However, previous studies failed to indicate volume expansion¹⁴ or an increased level of mineralocorticoids.¹⁵ To determine whether endogenous renal 11ß-HSD inhibitory factors may be involved in the pathophysiology of low-renin essential hypertension, we studied the urinary excretion of such inhibitors in patients with low-renin essential hypertension and compared the results with the effects of sodium restriction on the urinary excretion of endogenous renal 11ß-HSD inhibitory factors in normotensive subjects.

	Methods

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Protocol 1
Thirty Japanese patients with low-renin essential hypertension (18 men and 12 women; age range, 35 to 60 years) and 20 normotensive control subjects (12 men and 8 women; 31 to 58 years) were studied. Patients with uncomplicated low-renin essential hypertension who were admitted to the Kanazawa University Hospital were enrolled in the study, which was approved by the Hospital Ethics Committee. Patients were diagnosed as being hypertensive after three or more office readings of a systolic pressure greater than or equal to 160 mm Hg or a diastolic pressure greater than or equal to 95 mm Hg. Excluded from study were patients with secondary hypertension and indications of end-organ damage as evidenced by history, physical examination, electrocardiogram, and results of laboratory testing including urinalysis, measurement of serum creatinine and electrolytes, and when clinically relevant, determination of plasma and urinary levels of steroid hormones and catecholamines and results of renal imaging. Low-renin essential hypertension was diagnosed when the basal plasma renin activity was below the lower limit of normal, and when the plasma renin activity stimulated by oral administration of 80 mg furosemide and 4 hours of ambulation was less than the upper limit of 1 SD of the normal basal value (1.2±0.6 ng/L·s).¹⁶ Each patient ate a regular diet containing 180 mmol/d sodium and 60 mmol/d potassium during the study. All medications were withheld for at least 3 weeks. Patients abstained from smoking and alcohol consumption for 1 week before and also during the study.

Protocol 2
Six normotensive Japanese men (42 to 52 years old) were admitted to the Kanazawa University Hospital for study of the effect of sodium restriction on urinary excretion of renal 11ß-HSD inhibitory factor or factors. They received a normal diet containing 180 mmol sodium and 60 mmol potassium for 7 days, followed by 4 days of an isocaloric diet restricted to 50 mmol sodium and 60 mmol potassium. Urine samples were collected daily. Specimens used for steroid measurement were collected on the 7th day of the normal sodium diet and on the 4th day of the low sodium diet. Plasma samples were taken on the morning of the day of urine collection.

Informed consent was obtained from all subjects. The protocol was approved by the Human Research Committee of the Kanazawa University School of Medicine.

Steroid Measurements
The 24-hour urinary excretion of aldosterone was measured by radioimmunoassay after hydrolysis at pH 1 for 24 hours.¹⁷ Urinary 18-hydroxycorticosterone and free cortisol were measured by radioimmunoassay after HPLC purification of urine extracts as described previously.^{18 19} Plasma renin activity and plasma aldosterone were measured by radioimmunoassay, as previously described.²⁰ Urinary THE, THF, and allo-THF were measured with gas chromatography/mass spectrometry as previously described.²¹ Urinary electrolytes were measured by flame photometry.

Measurements of Urinary Endogenous Renal 11ß-HSD Inhibitory Factor or Factors
Urine Samples
A volume of 5 to 10 mL urine was passed through a prewashed (5 mL methanol, 10 mL water) Sep-Pak C18 cartridge (Waters) washed with 10 mL water and was eluted with 5 mL methanol. The methanol eluates were evaporated to dryness under nitrogen gas and then redissolved in 1 mL distilled water.

HPLC Purification of Urine Samples
For determination of the retention time of renal 11ß-HSD inhibitory factor or factors, urine extracts were diluted with methanol to a final concentration of 30% methanol and chromatographed on a C18 Ultrasphere ODS column (5 µm, Beckman Instruments). Components were eluted with a methanol gradient beginning with 30% aqueous methanol that increased linearly to 100% methanol by 60 minutes at a flow rate of 1 mL/min. Each fraction was evaporated under nitrogen gas and assayed for inhibitory activity in renal 11ß-HSD radioenzymatic assays. Urine extracts from patients and normotensive control subjects were purified with the HPLC system mentioned above, and fractions corresponding to the retention time of renal 11ß-HSD inhibitory factor were collected, evaporated under nitrogen gas, and measured for renal 11ß-HSD inhibitory activity.

Assay of Renal 11ß-HSD Inhibitory Activity
The radioenzymatic assay of renal 11ß-HSD inhibitory activity was performed by measuring the conversion of [³H]cortisol (specific activity, 83 Ci/mol; Amersham Japan) to [³H]cortisone with the method described by Morris et al⁹ with minor modifications.

Human kidney microsomes (0.14 mg protein) were incubated at 37°C for 10 minutes with 5 µmol/L cortisol and [³H]cortisol (1 µCi) as tracer in 50 mL Tris-HCl buffer (pH 8.5) containing 400 µmol/L NAD⁺ in a total volume of 0.25 mL, as previously described.²² Included in this volume was an aliquot of water (control), HPLC-purified urine samples, or GA. The reaction was terminated by addition of 4 mL ethyl acetate. Ethyl acetate extracts of the incubation media were evaporated to dryness under nitrogen gas, dissolved in 40% methanol, and chromatographed on a reversed-phase column with a solvent system (water/methanol/tetrahydrofuran, 52:40:8, vol/vol/vol) at a flow rate of 1.5 mL/min. The retention times of cortisol and cortisone were 24 and 19 minutes, respectively. The eluted fractions corresponding to cortisol and cortisone were collected by a fraction collector. Tritium-labeled steroids were counted in a liquid scintillation counter, and the percentage of conversion of cortisol to cortisone was calculated.

To provide a basis for measurement of the inhibitory activity of renal 11ß-HSD present in urine, aliquots of GA were added to the control inhibition mixtures in varying amounts (0 to 100 pmol). The percent inhibition was calculated relative to that of control (without GA) as previously described.⁹ Briefly, the percent inhibition owing to the urine extract was converted to picomoles of GA (GA equivalence units) with the appropriate GA standard curve. The variation of recovery and inter-array and intra-assay coefficients of variation of the assay were estimated with the use of known concentrations of urinary renal 11ß-HSD inhibitory factor or factors. A portion of normal kidney was obtained from a patient suffering from small renal cancer for use in the assay.

Statistics
Data are presented as mean±SEM. Hypertensive and control groups were compared by two-tailed unpaired Student's t tests. Wilcoxon's t test was used for paired data. Partial coefficients of correlation were calculated between the urinary excretion of the 11ß-HSD inhibitory factor(s), ratio of urinary THF+allo-THF to THE, and urinary excretion of sodium. A value of P<.05 was accepted as statistically significant.

	Results

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Endogenous renal 11ß-HSD inhibitory activity as determined by HPLC analysis peaked at 25 to 29 minutes (Fig 1). The standards for cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, and 11- and 11ß-hydroxyprogesterone were eluted at higher concentrations of methanol compared with the 11ß-HSD inhibitory activity peak.

View larger version (14K): [in this window] [in a new window]   Figure 1. HPLC profile shows endogenous renal 11ß-HSD inhibitory factor(s) (11ß-HSDIF).

As shown in Table 1, plasma levels and the urinary excretion of aldosterone and free cortisol as well as the (THF+allo-THF)/THE ratio did not differ significantly between the patients with low-renin essential hypertension and normotensive control subjects. Serum potassium concentration did not differ in the two groups, but the ratio of urinary sodium to potassium tended to be decreased in the low-renin essential hypertensive group. Urinary excretion of endogenous renal 11ß-HSD inhibitory factor(s) was significantly increased in patients with low-renin essential hypertension (1280±88 nmol/d) compared with normotensive control subjects (704±56 nmol/d, P<.05) (Fig 2). The urinary excretion of the inhibitory factor(s) was positively correlated with the urinary excretion of sodium (r=.54, P<.05) in all subjects. There was no significant correlation between the endogenous renal 11ß-HSD inhibitory factor(s) and the (THF+allo-THF)/THE ratio (data not shown).

View this table: [in this window] [in a new window]   Table 1. Serum and Urinary Parameters in Patients With Low-Renin Essential Hypertension and Normotensive Subjects

View larger version (15K): [in this window] [in a new window]   Figure 2. Plot shows urinary excretion of endogenous renal 11ß-HSD inhibitory factor(s) (11ß-HSDIF) in patients with low-renin essential hypertension (LRHT) and normotensive control subjects. Urinary excretion of endogenous renal 11ß-HSD inhibitory factor(s) was significantly greater in hypertensive patients than control subjects (P<.05).

The restricted sodium diet given to the six normotensive subjects for 4 days produced a significant increase in plasma renin activity and plasma aldosterone concentration (both P<.05) (Table 2). Data showed that urinary free cortisol and the (THF+allo-THF)/THE ratio did not differ in subjects on the normal versus the low sodium diet. The urinary endogenous renal 11ß-HSD inhibitory factor during the normal sodium diet was 738±95 nmol/d; after sodium restriction, the value decreased significantly to 432±51 nmol/d (P<.05) (Fig 3).

View this table: [in this window] [in a new window]   Table 2. Urinary and Plasma Parameters in Response to Restricted Sodium Intake

View larger version (17K): [in this window] [in a new window]   Figure 3. Plot shows effect of sodium restriction on urinary excretion of endogenous renal 11ß-HSD inhibitory factor(s) (11ß-HSDIF) in normotensive subjects (n=6). A low sodium diet (50 mmol/d) significantly reduced urinary excretion of endogenous renal 11ß-HSD inhibitory factor(s) compared with a normal sodium diet (180 mmol/d) (P<.05).

	Discussion

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Increasing evidence supports a contributory role of 11ß-HSD in hypertension. Barker et al²³ reported that hypertension is strongly predicted by the combination of low birth weight and a large placenta. Edwards et al²⁴ reported that placental 11ß-HSD activity was correlated directly with birth weight and inversely with placental weight. Fetuses with low birth weight and high placental weight (which are at the highest risk of hypertension as adults) had the lowest 11ß-HSD activity and presumably, therefore, the greatest exposure to maternal glucocorticoids.

The etiology of low-renin essential hypertension is unknown. Dahl salt-sensitive hypertensive rats show lower renin levels in the plasma, kidney, and adrenals than do Dahl salt-resistant rats.^{25 26} We previously reported that the activity of 11ß-HSD is decreased in Dahl salt-sensitive hypertensive compared with Dahl salt-resistant rats.²⁷

The excretion of endogenous 11ß-HSD inhibitory factor or factors has been reported in human urine. GA, the active agent in licorice root, markedly inhibits 11ß-HSD when incubated with this enzyme. Morris et al⁹ quantified this 11ß-HSD inhibitory factor (GALFs) using rat liver microsome and reported its increased excretion in pregnancy. Walker et al¹⁰ reported that GALFs had no diurnal rhythm and were unaffected by dexamethasone treatment in patients with low ACTH or with ectopic ACTH secretion. They also reported that in hypertensive patients associated with impaired 11ß-HSD activity, GALFs did not correlate with blood pressure and therefore concluded that GALFs were unlikely to play a role in the pathophysiology of hypertension.¹¹

The type 2 isoform of 11ß-HSD is thought to be responsible for protecting the renal mineralocorticoid receptors from cortisol and for contributing to the classic syndrome of apparent mineralocorticoid excess.¹² Mutations in the gene for the kidney isozyme of 11ß-HSD recently were found in patients with apparent mineralocorticoid excess.^{28 29} We used urine extracts to inhibit NAD⁺-dependent 11ß-dehydrogenase activity (type 2 isoform) in homogenized human kidney (ie, renal 11ß-HSD inhibitory factor). In our study, the endogenous renal 11ß-HSD inhibitory factor was significantly increased in patients with low-renin essential hypertension compared with control subjects. There were no significant differences in the urinary (THF+allo-THF)/THE ratio between the two groups. Plasma and urinary aldosterone levels were not elevated in the low-renin essential hypertensive group. Although the serum potassium concentration did not differ in the two groups, the ratio of urinary sodium to potassium tended to be decreased in the group with low-renin essential hypertension. These findings suggest that the endogenous renal 11ß-HSD inhibitory factor may contribute to the pathogenesis of low-renin essential hypertension by modulating type 2 11ß-HSD activity. Soro et al³⁰ reported that the ratio of THF+allo-THF to THE was higher in subjects with untreated essential hypertension than in control subjects. However, they did not measure urinary sodium excretion. Walker et al⁵ and Iki et al²¹ found no differences in the ratio of THF+allo-THF to THE between hypertensive and normotensive subjects. Walker et al reported that half-life periods of 11-[-H³]cortisol were prolonged in a subgroup of hypertensive patients, whose ratio of THF+allo-THF to THE did not differ from that of normotensive subjects. Therefore, the urinary metabolite ratio of THF+allo-THF to THE may not be a sensitive marker of renal 11ß-HSD activity.

Our study showed a positive correlation between the urinary excretion of the endogenous renal 11ß-HSD inhibitory factor or factors and the urinary excretion of sodium. If the activity of renal 11ß-HSD was inhibited by these factors, the urinary excretion of sodium would be decreased because of a state of hypermineralocorticoidism in the kidney. The amount of sodium excreted daily in the urine is inversely related to the amount of aldosterone excreted; however, the correlation is not significant at aldosterone excretion levels less than 10 µg/d (normal level of aldosterone).³¹ Renal 11ß-HSD activity is influenced by factors such as insulin, ethanol, furosemide, and angiotensin-converting enzyme inhibitors.^{32 33 34} Our protocol 2 in normotensive subjects showed that sodium restriction reduced the urinary excretion of the endogenous renal 11ß-HSD inhibitory factor or factors. The increase in angiotensin II produced by sodium restriction may not affect the endogenous renal 11ß-HSD inhibitory factor(s). Sodium may directly or indirectly influence the activity of 11ß-HSD by modulating the endogenous renal 11ß-HSD inhibitory factor(s). Data suggest that the elevation of endogenous renal 11ß-HSD inhibitory factor(s) observed in the hypertensive patients in the present study may have been a secondary effect of humoral factors. The chemical structure of the endogenous renal 11ß-HSD inhibitory factor or factors requires further study.

	Selected Abbreviations and Acronyms

 

11ß-HSD = 11ß-hydroxysteroid dehydrogenase GA = glycyrrhetinic acid GALF = glycyrrhetinic acid–like factor HPLC = high-performance liquid chromatography THE = tetrahydrocortisone THF = tetrahydrocortisol

Received July 11, 1995; first decision August 25, 1995; accepted October 27, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Monder C, Shackleton CHL. 11ß-Hydroxysteroid dehydrogenase: fact or fancy? Steroids. 1984;44:383-417. [Medline] [Order article via Infotrieve]

2. Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosler A, Bradlow HL, New MI. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab. 1979;49:757-764. [Abstract/Free Full Text]

3. Stewart PM, Valentino R, Wallace AM, Burt D, Shackleton CHL, Edwards CRW. Mineralocorticoid activity of liquorice: 11-ß-hydroxysteroid dehydrogenase deficiency comes of age. Lancet. 1987;2:821-824. [Medline] [Order article via Infotrieve]

4. Stewart PM, Wallace AM, Atherden SM, Shearing CH, Edwards CRW. Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11ß-hydroxysteroid dehydrogenase activity in man. Clin Sci. 1990;78:49-54. [Medline] [Order article via Infotrieve]

5. Walker BR, Stewart PM, Shackleton CHL, Padfield PL, Edwards CRW. Deficient inactivation of cortisol by 11ß-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol. 1993;39:221-227. [Medline] [Order article via Infotrieve]

6. Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Iki K, Takeda R. Decreased activity of 11ß-hydroxysteroid dehydrogenase in mesenteric arteries of Dahl salt-sensitive rats. Life Sci. 1994;54:1343-1349. [Medline] [Order article via Infotrieve]

7. Takeda Y, Yoneda T, Miyamori I, Gathiram P, Takeda R. 11ß-Hydroxysteroid dehydrogenase activity in mesenteric arteries of spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1993;20:627-631. [Medline] [Order article via Infotrieve]

8. Agarwal AK, Mune T, Monder C, White PC. NAD⁺-dependent isoform of 11ß-hydroxysteroid dehydrogenase. J Biol Chem. 1994;269:25959-25962. [Abstract/Free Full Text]

9. Morris DJ, Semafuko WEB, Latif SA, Vogel B, Grimes CA, Sheff MF. Detection of glycyrrhetinic acid–like factors (GALFs) in human urine. Hypertension. 1992;20:346-360.

10. Walker BR, Aggarwal ILA, Stewart PM, Padfield PL, Edwards CRW. Endogenous inhibitors of 11ß-hydroxysteroid dehydrogenase in hypertension. J Clin Endocrinol Metab. 1995;80:529-533. [Abstract]

11. Walker BR, Williamson PM, Brown MA, Honour JW, Edwards CRW, Whitworth JA. 11ß-Hydroxysteroid dehydrogenase and its inhibitors in hypertensive pregnancy. Hypertension. 1995;25:626-630. [Abstract/Free Full Text]

12. Benediktsson R, Walker BR, Edwards CRW. Cellular selectivity of aldosterone: role of 11 beta-hydroxysteroid dehydrogenase. Curr Opin Nephrol Hypertens. 1995;4:41-46. [Medline] [Order article via Infotrieve]

13. Kaplan NM. Primary hypertension: pathogenesis. In: Retford DC, ed. Clinical Hypertension. 6th ed. Baltimore, Md: Williams & Wilkins; 1994:47-108.

14. Lebel M, Schalekamp MA, Beevers DG. Sodium and the renin-angiotensin system in essential hypertension and mineralocorticoid excess. Lancet. 1974;2:308-310. [Medline] [Order article via Infotrieve]

15. Gomez-Sanchez CE, Holland OB, Upcavage R. Urinary free 19-nor-deoxycorticosterone and deoxycorticosterone in human hypertension. J Clin Endocrinol Metab. 1985;60:234-238. [Abstract/Free Full Text]

16. Takeda R, Morimoto S, Uchida K, Hashiba T, Kigoshi T, Honjo A, Fujimura A. Aldosterone responsiveness to angiotensin II after sodium restriction in subjects with low renin essential hypertension. Clin Exp Hypertens A. 1982;4:937-949. [Medline] [Order article via Infotrieve]

17. Takeda Y, Miyamori I, Takeda R, Lewicka S, Vecsei P. Effect of sodium restriction on urinary excretion of 19-noraldosterone and 18,19-dihydroxycorticosterone, newly identified mineralocorticoids in man. J Clin Endocrinol Metab. 1992;74:1195-1197. [Abstract]

18. Takeda Y, Miyamori I, Iki K, Takeda R, Vecsei P. Urinary excretion of 19-noraldosterone, 18,19-dihydroxycorticosterone and 18-hydroxy-19-norcorticosterone in patients with aldosterone-producing adenoma or idiopathic hyperaldosteronism. Acta Endocrinol. 1992;126:484-488.

19. Takeda Y, Karayalcin U, Miyamori I, Takeda R. Influence of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor, pravastatin, on corticosteroid metabolism in patients with heterozygous familial hypercholesterolemia. Horm Res. 1991;36:75-77. [Medline] [Order article via Infotrieve]

20. Takeda R, Morimoto S, Uchida K, Miyamori I. Changes in plasma renin activity and plasma aldosterone in the induced paralytic attack of thyrotoxic periodic paralysis. Acta Endocrinol. 1976;82:715-727.

21. Iki K, Miyamori I, Hatakeyama H, Yoneda T, Takeda Y, Takeda R, Dai QI. The activities of 5ß-reductase and 11ß-hydroxysteroid dehydrogenase in essential hypertension. Steroids. 1994;59:656-660.[Medline] [Order article via Infotrieve]

22. Stewart PM, Murry BA, Mason JI. Human kidney 11ß-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. J Clin Endocrinol Metab. 1994;79:480-484.[Abstract]

23. Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990;301:259-262.

24. Edwards CRW, Benediktsson R, Lindsay RS, Seckl JR. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet. 1993:341:355-357.

25. Iwai J, Dahl LK, Knudsen KD. Genetic influence on the renin-angiotensin system. Circ Res. 1973;32:678-684. [Abstract/Free Full Text]

26. Baba K, Mulrow PJ, Franco-Saenz R, Rapp JP. Suppression of adrenal renin in Dahl salt-sensitive rats. Hypertension. 1986;8:1149-1153. [Abstract/Free Full Text]

27. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Takeda R. Gene expression of 11ß-hydroxysteroid dehydrogenase in the mesenteric arteries of genetically hypertensive rats. Hypertension. 1994;23:577-580. [Abstract/Free Full Text]

28. Wilson RC, Krozowski ZS, Li K, Obeyesekere VR, Razzaghy-Azar M, Harbison MD, Wei JQ, Shackleton CHL, Funder JW, New MI. A mutation in the HSDB2 gene in a family with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 1995;80:2263-2266. [Abstract]

29. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme dehydrogenase. Nat Genet. 1995;10:394-399. [Medline] [Order article via Infotrieve]

30. Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R. Evidence of coexisting changes in 11ß-hydroxysteroid dehydrogenase and 5ß-reductase activity in subjects with untreated essential hypertension. Hypertension. 1995;25:67-70. [Abstract/Free Full Text]

31. Ross EJ. Biological role of aldosterone in homeostasis. In: Ross EJ, ed. Aldosterone and Aldosteronism. London, UK: Lloyd-Luke Ltd; 1975:192-207.

32. Riddle MC, McDaniel PA. Acute reduction of renal 11ß-hydroxysteroid dehydrogenase activity by several antinatriuretic stimuli. Metabolism. 1993;42:1370-1374. [Medline] [Order article via Infotrieve]

33. Escher G, Meyer KV, Vishwanath BS, Frey BM, Frey FJ. Furosemide inhibits 11ß-hydroxysteroid in vitro and in vivo. Endocrinology. 1995;136:1759-1765.[Abstract]

34. Riddle MC, McDaniel PA. Renal 11ß-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril. J Clin Endocrinol Metab. 1994;78:830-834.[Abstract]

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