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(Hypertension. 1996;27:421-425.)
© 1996 American Heart Association, Inc.

Articles

11- and 11ß-Hydroxyprogesterone, Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase, Possess Hypertensinogenic Activity in the Rat

Graham W. Souness; David J. Morris

From the Department of Pathology and Laboratory Medicine, The Miriam Hospital, and the Division of Biology and Medicine, Brown University, Providence, RI.

Correspondence to Graham W. Souness, PhD, The Miriam Hospital, Department of Pathology and Laboratory Medicine, 164 Summit Ave, Providence, RI 02906.

	Abstract

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Abstract The progesterone derivatives 11- and 11ß-hydroxyprogesterone are potent inhibitors of 11ß-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11ß-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11ß-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure–modulating effects of 11- and 11ß-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11- and 11ß-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11- and 11ß-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11ß-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11ß-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.

Key Words: progesterone • corticosterone • 11ß-hydroxysteroid dehydrogenase • hypertension, experimental

	Introduction

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We have recently demonstrated that a variety of steroid derivatives, some of which are endogenous, not only inhibit the enzyme 11ß-HSD but can also confer mineralocorticoid Na⁺-retaining activity on the glucocorticoid corticosterone.¹ 11ß-HSD is an important steroid-inactivating enzyme that metabolizes the C₁₁-OH–containing hormones cortisol in humans and corticosterone in the rat to their respective inactive 11-keto products cortisone and 11-dehydrocorticosterone.^{2 3} This enzyme, which has so far been shown to exist in two isoforms,^{4 5} is present in several tissues, such as kidney, liver, and lung; importantly, its action in the kidney and other mineralocorticoid target tissues allows aldosterone specificity by preventing cortisol and corticosterone from accessing MRs.^{6 7} The presence of 11ß-HSD activity in the kidney has been suggested to be important not only in the control of Na⁺ retention^{8 9} but, along with 11ß-HSD activity in vascular tissue and brain, in the control of BP.^{10 11 12 13 14}

11ß-HSD1, the first isoform described, was initially isolated from liver, although it is also present in rat renal proximal tubules; it uses NADP⁺ as a cofactor, has a K_m for corticosterone of approximately 2 µmol/L, and is, at least in the liver, bidirectional.¹⁵ The 11ß-HSD isoform in vascular smooth muscle preparations is also bidirectional; however, its K_m for corticosterone is significantly lower than that of hepatic 11ß-HSD1.¹⁶

By contrast, 11ß-HSD2 is NAD⁺ dependent, unidirectional, has a K_m for corticosterone of 20 to 40 nmol/L, and is subject to end-product inhibition.⁵ Importantly, 11ß-HSD2 is found in distal portions of the nephron where it has been shown to be colocalized with MRs.^{5 17 18} The existence of a third 11ß-HSD isoform, which also has a K_m for corticosterone in the nanomolar range but which is NADP⁺ dependent, has recently been suggested; however, its identification remains to be elucidated.¹⁹

In our most recent studies,²⁰ we have demonstrated that both the progesterone derivatives 11- and 11ß-OHP are not only potent inhibitors of 11ß-HSD1 and 11ß-HSD2 activities in vitro but are extremely active in conferring mineralocorticoid Na⁺-retaining activity on corticosterone in vivo in a rat bioassay. We undertook the present studies to determine what effects these potent 11ß-HSD inhibitors might have on the BP of intact rats.

	Methods

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SD rats (125 to 150 g body weight) and SHR (3 weeks of age) were obtained from Charles River Laboratories (Wilmington, Mass). All rats drank tap water ad libitum. SD rats were maintained on standard rat chow, and SHR were fed a customized diet containing 0.1% Na⁺ (Pro-Lab). All experimental procedures were in accordance with our institutional guidelines.

Before the start of experimentation, rats were handled extensively and had their BP taken so they became used to this procedure. Implanted miniosmotic pumps (Alzet 2002, Alza Corp) were used for subcutaneous infusions. Each pump delivered 0.5±0.02 µL/h for 14 days and was implanted with rats under metofane (Pitman-Moore) anesthesia. BP was measured the day before pumps were implanted and on days 3, 7, 10, and 14 after implantation. Indirect systolic BPs were measured with a modified tail-cuff method. A photoelectric-oscillometric BP sensor incorporated into a tail cuff connected to an automatic cuff inflation pump (IITC) was used to detect the BP at ambient temperature. BP was determined as the mean of at least four measurements. Rats were weighed once a week throughout the experiments.

Effect of 11- and 11ß-OHP on BP in Intact SD Rats
11- and 11ß-OHP were dissolved in propylene glycol (100%) and infused at 3 and 10 µg/h, respectively, for 14 days. Control rats received vehicle only.

11-OHP (3 µg/h) together (in the same miniosmotic pump) with the specific MR antagonist RU28318 (40 µg/h) was infused in propylene glycol over 14 days. The control group received 11-OHP alone.

Effect of 11-OHP in Adrenalectomized SD Rats
11-OHP (3 µg/h) or propylene glycol alone was infused into two groups of rats that had been adrenalectomized at the same time as the miniosmotic pumps were implanted. These rats were given 0.154 mol/L saline to drink for the duration of the experiment.

Effect of 11-OHP in SHR
SHR begin to develop hypertension at approximately 5 weeks of age unless they are adrenalectomized before or up to this point, when they will then remain normotensive. Reintroduction of corticosterone or aldosterone by continuous infusion will restore the hypertension in these adrenalectomized SHR.²¹ We examined the effects of 11-OHP on the development of hypertension induced by corticosterone in adrenalectomized SHR. At 5 weeks of age, male SHR were adrenalectomized and miniosmotic pumps were implanted subcutaneously. Rats received either vehicle (propylene glycol), corticosterone (10 µg/h), or a combination of 11-OHP (20 µg/h) and corticosterone (10 µg/h) for 14 days. Rats were maintained on 0.154 mol/L NaCl after adrenalectomy. BP was measured before adrenalectomy and pump implantation and then twice a week thereafter.

Rats were killed at the end of each experiment by CO₂ narcosis and asphyxiation, and the miniosmotic pumps were removed and examined for verification that their contents had been delivered. There were five rats in each experimental group. Data were analyzed by ANOVA and the Bonferroni t test. 11- and 11ß-OHP were obtained from Steraloids and corticosterone from Sigma Chemical Co; RU28318 was a gift from Rousell Uclaf.

	Results

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Effects in SD Rats
The continuous subcutaneous infusion of both 11-OHP (3 µg/h) and 11ß-OHP (10 µg/h) significantly increased BP in intact SD rats (Fig 1). An elevated BP was seen within 3 days; and by day 7, 11- and 11ß-OHP gave mean BPs of 143±5 and 149±2 mm Hg, respectively, compared with 113±3 mm Hg for the control group. The maximal hypertensive effect was achieved by day 7; after this point the mean BP fell slightly in rats treated with both 11- and 11ß-OHP.

View larger version (20K): [in this window] [in a new window]   Figure 1. Line graph shows effects on indirect systolic BP of a continuous subcutaneous infusion of 11-OHP at 3 µg/h and 11ß-OHP at 10 µg/h in intact SD rats. Each compound was infused for 14 days starting on day 0. BP was measured the day before infusion pumps were implanted (see "Methods") and twice a week thereafter. Control (CTRL) rats received vehicle only (propylene glycol). Values are mean±SEM; n=5 rats per group. *P<.05 vs control group.

In experiments in which 11-OHP (3 µg/h) was continuously infused subcutaneously together with the specific mineralocorticoid antagonist RU28318 (40 µg/h), the hypertensinogenic actions of 11-OHP were significantly blunted (Fig 2). In this group the mean BP rose to approximately 120 to 123 mm Hg by day 3, an effect similar to that of 11-OHP alone; however, the mean BP decreased after day 3 and throughout the remainder of the experiment. The mean BP in this group was not significantly different from that of the control group.

View larger version (20K): [in this window] [in a new window]   Figure 2. Line graph shows effects on indirect systolic BP of a continuous 14-day subcutaneous infusion of 11-OHP (3 µg/h) both alone and together with the specific mineralocorticoid antagonist RU28318 (40 µg/h) in intact SD rats. Control (CTRL) rats received vehicle only (propylene glycol). Values are mean±SEM; n=5 rats per group. *P<.05 vs control group.

In adrenalectomized rats, the hypertensinogenic effects of 11-OHP (3 µg/h) alone were abolished (Fig 3). At no time in the experiment was the mean BP in the experimental group significantly different from the BP of the control adrenalectomized rats; the maximum mean BP achieved by this dose of 11-OHP was 115.7±4 mm Hg compared with 118.9±2 mm Hg in the control (adrenalectomized) group.

View larger version (21K): [in this window] [in a new window]   Figure 3. Line graph shows effects on indirect systolic BP of a continuous 14-day subcutaneous infusion of 11-OHP (3 µg/h) in both intact and adrenalectomized (ADX) SD rats. Control adrenalectomized rats (ADX-CTRL) received propylene glycol. Values are mean±SEM; n=5 rats per group. *P<.05 vs ADX-CTRL and ADX+11-OHP groups.

Effects in SHR
Adrenalectomized SHR failed to develop hypertension, as previously described²¹ (Fig 4). A continuous infusion of corticosterone at 10 µg/h SC for 14 days into adrenalectomized SHR restored the pattern of hypertension to that observed in intact SHR, increasing the average BP to approximately 150 mm Hg by day 14. When 11-OHP (20 µg/h) was infused together with corticosterone, the hypertensive action of the latter was significantly enhanced by 20 to 30 mm Hg. This amplification in BP was seen by day 7 and persisted for the duration of the experiment (Fig 4). In a separate experiment, the same dose of 11-OHP alone infused over 14 days had no effects on BP in adrenalectomized SHR (data not shown).

View larger version (19K): [in this window] [in a new window]   Figure 4. Line graph shows effects on indirect systolic BP of a continuous 14-day subcutaneous infusion of corticosterone (B, 10 µg/h) alone or together with 11-OHP (20 µg/h) in adrenalectomized (ADX) SHR. Control rats received vehicle only. Values are mean±SEM; n=5 rats per group. *P<.05 vs corticosterone alone.

	Discussion

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Several important studies have led to the hypothesis that changes in 11ß-HSD activity are key to the anomalous regulation of Na⁺ retention by glucocorticoids. The studies of Ulick et al^{22 23} have clearly shown that children with apparent mineralocorticoid excess syndrome have a specific defect, with markedly diminished 11ß-HSD activity leading to Na⁺ retention, hypokalemia, and low plasma aldosterone and renin levels. When treated with cortisol, these children developed Na⁺ retention and a marked increase in BP, indicating that cortisol was acting as a mineralocorticoid.²⁴ The subsequent experiments of Stewart et al⁸ demonstrated that the hypertension caused by excessive licorice ingestion was also due to diminished 11ß-HSD activity caused by glycyrrhetinic acid inhibition of this enzyme. The earlier work of Kornel et al^{10 11} also indicated that impaired 11ß-HSD activity may play a role in essential hypertension by showing altered ratios of cortisol to cortisone in both the serum and urine of these patients. Moreover, in clinical experiments conducted on essential hypertensive patients, the plasma half-life of 11-[³H]cortisol was prolonged, a finding also consistent with lowered 11ß-HSD activity.²⁵

It is widely accepted that 11ß-HSD acts as a "guardian" in the kidney, as originally proposed by Edwards et al⁶ and Funder et al.⁷ Furthermore, as an expansion on this original theory, it is now believed that the low-K_m, unidirectional 11ß-HSD2 and possibly 11ß-HSD1 prevent glucocorticoids from binding to renal MRs and eliciting mineralocorticoid electrolyte transport.⁵ Several studies have shown that the licorice derivatives glycyrrhetinic acid and carbenoxolone, which potently inhibit both 11ß-HSD1 and 11ß-HSD2, can confer significant Na⁺-retaining activity on cortisol and corticosterone (via MR-mediated processes) in both rat and isolated toad bladder preparations.^{26 27 28}

In the present studies, we have demonstrated that both 11ß- and 11-OHP possess hypertensinogenic properties in intact SD rats, causing significant increases in their BPs. The doses used for these infusions were similar to those described by Gomez-Sanchez and Gomez-Sanchez¹³ for the daily dose of carbenoxolone that caused hypertension in intact normotensive SD rats. The hypertensinogenic effects of 11-OHP were not observed when infusions were performed in adrenalectomized rats, strongly suggesting that the presence of an intact adrenal is necessary for these progesterone derivatives to increase BP. In addition, the hypertensinogenic effects of 11-OHP were blunted in rats concomitantly treated with the specific MR antagonist RU28318, indicating that the processes controlling the increase in BP are mediated at least in part by MRs. 11-OHP also significantly amplified the hypertension seen when adrenalectomized SHR were infused with corticosterone.

We have previously demonstrated that both 11- and 11ß-OHP are very potent inhibitors of 11ß-HSD1 and 11ß-HSD2 in vitro and that they confer significant Na⁺-retaining activity on corticosterone in adrenalectomized rats²⁰ ; this latter effect was again inhibited by RU28318. These findings, taken together with the results of the present experiments, would seem to suggest that the inhibition of renal 11ß-HSD by these progesterone derivatives allows corticosterone to access renal MRs, causing significant Na⁺ retention, an effect that over time can lead to the development of hypertension in the SD rat. However, it is entirely possible that the hypertensinogenic properties of 11- and 11ß-OHP are not necessarily limited to their actions on corticosterone metabolism but may depend on contributions from other adrenal steroid hormones or even steroid intermediates that may not operate solely through MRs. Indeed, the pattern of hypertension observed in the current experiments resembles that seen when 11ß-HSD inhibitors such as carbenoxolone are administered: a 3- to 5-day onset of hypertension and a plateau at 7 to 10 days as opposed to the hypertension that develops in rats infused with mineralocorticoids, which has an onset of 7 to 10 days and steadily increases over weeks.²⁹ It has also been suggested that when 11ß-HSD activity is inhibited, glucocorticoid receptors can be recruited to mediate mineralocorticoid effects.³⁰

In addition, it is not possible to determine at this time the relative contributions to the increased BP that can result from enhanced renal Na⁺ retention or from inhibition of 11ß-HSD known to be present in the brain³¹ and vascular smooth muscle.³² Recent experiments have shown that carbenoxolone can cause significant hypertension in normotensive SD rats when infused into the cerebral ventricles, an effect inhibited by RU28318.¹³ Nonetheless, the current experiments emphasize that these potent 11ß-HSD inhibitors do possess hypertensinogenic properties, and further experimentation is necessary to determine the action of these important substances at the renal, vascular smooth muscle, and brain levels.

Both 11ß- and 11-OHP, probably by virtue of their C₁₁-OH group, are potent inhibitors of 11ß-HSD. Many of the other progesterone metabolites, eg, pregnanediol, which lack this functional group, have much less or no inhibitory activity toward this enzyme.²⁰ 11ß-OHP is an endogenous progesterone metabolite that can serve as substrate for 11ß-HSD and thus acts as a potent competitive inhibitor of this enzyme. 11-OHP is not endogenous and has been shown not to be a substrate for the enzyme²⁰ and likely inhibits 11ß-HSD in a noncompetitive manner. However, if shown to be present in humans, 11-OHP would most likely be a product of bacterial enzymes in the gut and could be of major significance. 11ß-OHP is produced in the adrenal gland under certain clinical conditions, eg, 17-hydroxylase deficiency,^{33 34} and has recently been suggested to be synthesized in vascular tissues.³⁵ Whether or not the synthesis of these progesterone metabolites is shown to be altered in hypertensive states, these and similar substances will serve as valuable tools in understanding the biochemical mechanisms operating in the regulation of glucocorticoid-induced Na⁺ retention and BP.

	Selected Abbreviations and Acronyms

 

BP = blood pressure HSD = hydroxysteroid dehydrogenase MR = mineralocorticoid receptor OHP = hydroxyprogesterone SD = Sprague-Dawley SHR = spontaneously hypertensive rat(s)

	Acknowledgments

 
This work was supported by National Institutes of Health grant DK21404 and the Miriam Hospital Research Foundation.

Received September 9, 1995; first decision October 18, 1995; accepted November 24, 1995.

	References

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