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J Am Soc Nephrol 13:191-196, 2002
© 2002 American Society of Nephrology

Glycyrrhetinic Acid Decreases Plasma Potassium Concentrations in Patients with Anuria

Andreas Serra, Dominik E. Uehlinger, Paolo Ferrari, Bernhard Dick, Brigitte M. Frey, Felix J. Frey and Bruno Vogt

University Hospital of Berne, Berne, Switzerland.

Correspondence to Dr. Bruno Vogt, Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland. Phone: 4131-632-3144; Fax: 4131-632-9734; E-mail: bruno.vogt{at}insel.ch


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. Licorice-associated hypertension is thought to be due to increased renal sodium retention. The active compound of licorice, glycyrrhetinic acid (GA), inhibits renal 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) and by that mechanism increases access of cortisol to the mineralocorticoid receptor that causes renal sodium retention and potassium loss. In addition, a direct vascular effect of 11ß-HSD activity has recently been incriminated to promote hypertension, a contention based on in vitro observations. This investigation was designed to establish whether this extrarenal effect of 11ß-HSD is relevant for BP regulation and potassium concentrations in plasma. In a prospective, double-blind, cross-over study, seven patients with anuria on chronic hemodialysis were randomly assigned after a baseline period of 2 wk to placebo or GA (1 g/d) for 2 wk, separated by a washout phase of 3 wk. The ratio of plasma cortisol/cortisone, determined by gas chromatography–mass spectrometry, increased in all patients after GA intake (F = 9.705; P < 0.004), which indicates inhibition of 11ß-HSD. Twenty-four–hour BP values did not change throughout the study. The increase of the plasma cortisol/cortisone ratio was paralleled by a decline in the plasma potassium concentration in every patient. The mean ± SD plasma potassium concentration decreased from 5.5 ± 0.6 mM/L at baseline to 4.9 ± 0.7 and 4.5 ± 0.8 mM/L after 1 and 2 wk on GA, respectively (F = 9.934, P < 0.003). Extrarenal 11ß-HSD activity influences serum potassium concentrations but does not regulate BP independently of renal sodium retention.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The ingestion of licorice causes hypokalemic hypertension with low renin and low aldosterone concentrations. The mechanism of this hypertension is the inhibition of the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) by glycyrrhetinic acid (GA), the active ingredient of licorice (1–3). 11ß-HSD2 catalyzes the dehydrogenation of 11ß-hydroxyglucocorticoids, has a nanomolar Km for cortisol, uses NAD+ as cofactor, and is localized in the endoplasmic reticulum membrane (4,5). The enzyme exhibits a cell-specific constitutive expression in mineralocorticoid target tissues, such as epithelial cells from the colon and the renal cortical collecting tubule (4,6), where it regulates the intracellular localization of the mineralocorticoid receptor (MR) and protects the MR from promiscuous activation by 11ß-hydroxyglucocorticoids, including cortisol (2,3,7,8). Loss of function mutation or inhibition of 11ß-HSD2 allows glucocorticoids to promote renal sodium retention and potassium excretion in the cortical collecting tubule, with subsequent volume expansion, hypertension, and suppression of renin and aldosterone (9–11).

Recent evidence has suggested that the increase in BP associated with decreased 11ß-HSD2 activity is not only because of enhanced renal sodium retention but also a direct vascular effect (12–14). Expression of 11ß-HSD2 is found in human vascular smooth-muscle cells (15). In these cells, inhibition or downregulation with an antisense DNA of 11ß-HSD2 increased the glucocorticoid induced vascular angiotensin II binding (15). In intact rat vascular rings, the contractile response to angiotensin II and catecholamines was enhanced when the dehydrogenase reaction of 11ß-HSD was inhibited by licorice derivatives (12,13,15). Furthermore, skin vasoconstriction of cortisol was shown to be potentiated by the 11ß-HSD inhibitor GA in humans (16). Whether and to what extent these extrarenal effects of 11ß-HSD2 are relevant for BP regulation is unknown. To dissect the vascular from the renal tubular effect of 11ß-HSD2, we studied the impact of inhibition of 11ß-HSD2 with GA on the BP in patients with anuria on chronic hemodialysis.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and Study Design
A prospective, placebo-controlled, double-blind, crossover study approved by the local ethics committee was performed in 12 patients with anuria on chronic hemodialysis. All patients gave written informed consent. Three patients did not complete the study: one received a kidney transplant, one was operated for hip fracture, and one patient withdrew. Two patients were excluded from the study, one because of progesterone medication and one because of >10% dry weight gain during the placebo period. The remaining seven patients, three women and four men with a mean ± SD age of 58 ± 14 yr, had a body-mass index of 24 ± 6 and were dialysed three times weekly for 3.46 ± 0.37 h by use of polysulfone filters and dialysate that contained bicarbonate. Dialysis data are given in Table 1. The effective Kt/V was calculated according to the method of Daugirdas et al. (17,18). Dialysis prescriptions, dry body weight, and drug therapy were not changed throughout the study. The patients were instructed to avoid products with licorice.


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  		Table 1. Dialysis data
 
After a run-in phase of 2 wk, patients were randomized to either GA (500 mg) or placebo given twice daily for 14 d. After a washout phase of 3 wk, the groups crossed over. Hard gelatin capsules (No. 000; Eli Lilly Co., Indianapolis, IN) that contained 250 mg of 18ß-GA or saccharose (Fluka, Buchs, Switzerland) were manufactured by the pharmacy at the University Hospital (19).

Blood samples were obtained at the end of the run-in and washout phase as well as after 1 and 2 wk of placebo or GA intake. These blood samples were collected before start of the hemodialysis session after 10 min supine rest. The hemodialysis sessions chosen for blood collection were always those after the long hemodialysis interval of 3 d.

The 24-h ambulatory BP monitoring was performed with an automatic oscillometer (Profilomat 2; Disentronic Burgdorf, Switzerland) on the nonaccess arm at the end of the run-in, washout, and placebo and GA phases. BP was recorded every 15 min during the hemodialysis sessions, every 30 min during the daytime off dialysis, and every 60 min from 10:00 p.m. to 6:00 a.m. the next day.

Analysis of Plasma Steroid Metabolites by Gas Chromatography–Mass Spectrometry
To 1 ml of plasma, 2.5 µg of medroxyprogesterone was added as a recovery standard, and the sample was extracted with 10 ml of dichlormethane. After centrifugation, the phases were separated, and the organic phase (containing the unconjugated steroids) was evaporated under a stream of nitrogen at room temperature. A 2.5-µg volume of stigmasterol was added as an internal standard, and the sample was derived to form the methyloxime-trimethylsilyl ethers.

To the water phase (containing the conjugated steroids), 2.5 µg of medroxyprogesterone was added as a recovery standard. Plasma proteins were precipitated with 5 ml of methanol. After centrifugation, the supernatant was transferred into a new tube and evaporated under a stream of nitrogen at 60°C. The sample was reconstituted in 0.1 M acetate buffer, adjusted to pH 4.6, and hydrolyzed with powdered Helix pomatia enzyme (12.5 mg, Sigma) and 12.5 µl of ß-glucuronidase/arylsulfatase liquid enzyme (Boehringer Mannheim). The resulting free steroids were extracted on a SEP PAK C18 cartridge. To this extract, 2.5 µg of stigmasterol was added as an internal standard, and the sample was derived to form the methyloxim-trimethylsilyl ethers.

Fractions were analyzed by gas chromatography–mass spectrometry by use of a Hewlett-Packard gas chromatograph 6890 with a mass-selective detector 5973 by selective ion monitoring. One characteristic ion was chosen for each compound being measured. Mass 605 was monitored for cortisol and mass 531 for cortisone. A temperature-programed run from 210°C to 265°C over 35 min was chosen. Calibration lines were established over the range of 10 to 500 ng/ml. Correlation coefficients were >0.97. The results of cortisol and cortisone levels represent concentrations found as unconjugated cortisol and cortisone. Plasma renin and aldosterone were determined by RIA.

Statistical Analyses
Statistical analyses were performed with the statistical software package SYSTAT 9.0 for Windows (SPSS Inc., Chicago, IL). ANOVA was used to determine the effect of time and treatment with GA on measured parameters. Paired comparisons were done with the two-tailed t test.


   Results
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 Materials and Methods
 Results
Discussion
 References
 
BP and Body Weight
The 24-h BP measurements did not differ among the run-in, placebo, washout, and GA phases. To determine whether GA intake affected BP during the hemodynamic stress of hemodialysis, BP was measured during dialysis treatment. In Table 2, the BP values obtained at the end of the placebo and GA phase, as well as the percent change versus baseline, are given. Twenty-four-hour ambulatory BP values did not change throughout the study. The decline in BP at 2 and 3 h was independent of intake of GA (Table 2). The predialytic and postdialytic weight change were independent of GA (Table 3).


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  		Table 2. Mean ± SD BP (mm Hg) and heart rate (per min) of patients on hemodialysis with and without glycyrrhetinic acid for 2 wk and percentage of change versus baseline
 

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  		Table 3. Mean ± SD laboratory data and body weight in patients on hemodialysis (HD) with and without glycyrrhetinic acid
 
Laboratory Data
One and two weeks after daily ingestion of GA, the ratio of plasma cortisol/cortisone increased from 9.6 ± 2.2 to 14.7 ± 4.7 and 15.4 ± 5.7, respectively (F = 9.705, P < 0.004) (Figure 1). This increase was observed in every patient, independent of whether the run-in, placebo, or washout phase was considered as the baseline. In Table 3, the mean (±SD) values before and at the end of the placebo and GA phase are given. The increase in the cortisol/cortisone ratio was mainly due to a decline in cortisone concentrations (Table 3). After 2 wk of daily ingestion of GA, the mean (±SD) plasma aldosterone concentration was 74 ± 36, compared with 152 ± 148 pmol/L at the end of the placebo period (Table 3). This difference was statistically NS (P = 0.16). The corresponding plasma renin values were not affected by the intake of GA (Table 3).



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  		Figure 1. Plasma cortisol/cortisone ratios at baseline and 1 and 2 wk after the intake of glycyrrhetinic acid or placebo (mean ± SEM).

 
A decrease in plasma potassium was observed in every patient after 1 and 2 wk of GA, i.e., from mean ± SD values of 5.5 ± 0.6 mM/L at baseline to 4.9 ± 0.7 and 4.5 ± 0.8 mM/L after 1 and 2 wk, respectively (F = 9.934; P < 0.003) (Figure 2). This decrease was observed whether the run-in, placebo, or washout phase was considered the baseline. The decline in the plasma potassium concentration paralleled the increase in the cortisol/cortisone ratio in each patient (Figure 1; Table 3). A plot of the ratios of cortisol/cortisone versus the plasma potassium concentrations revealed a significant correlation when the values after 1 wk (R = 0.685; P < 0.05; Pearson two-tailed) or after 2 wk (R = 0.803; P < 0.01) were considered as a group. The other plasma and hematology parameters were not influenced by GA (Table 3).



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  		Figure 2. Plasma potassium concentrations at baseline and 1 and 2 wk after the intake of glycyrrhetinic acid or placebo (mean ± SEM).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present investigation reveals that BP does not increase when 11ß-HSD2 activity is significantly inhibited by GA in patients with anuria on hemodialysis. Compliance with the treatment regimen was demonstrated by the increased ratio of cortisol/cortisone in all subjects while on GA. The absence of an effect of GA on BP cannot be explained by changes in dietary habits, because body weight did not change as a function of time during the various study periods. Although unlikely, it is conceivable that an extrarenal effect of 11ß-HSD2 on BP was concealed by the uremic disease state in this study. For methodological reasons, however, it is not possible to investigate the relevance of extrarenal 11ß-HSD2 for BP control in subjects with a normal renal function. Thus, despite the methodological caveat, the notion that extrarenal 11ß-HSD2 is relevant for BP control (12,13,15) has to be reconsidered.

In patients with a loss of function mutation of 11ß-HSD2 or in subjects with an inhibited activity of 11ß-HSD2 by endobiotics or xenobiotics, the increase in BP is associated with activation of MR by cortisol (1,20–22). The same receptors can be activated by the mineralocorticoid fludrocortisone. This drug has been investigated elsewhere in patients on hemodialysis (23). In line with our observations, these patients did not exhibit an increase in BP or body weight (23). Thus, activation of MR is unlikely to increase BP independently of a functioning kidney. The two models, prescription of fludrocortisone and inhibition of 11ß-HSD2, however, cannot a priori be expected to yield the same biological effect, because inhibitors of 11ß-HSD2 enzymes do not only modulate access of endogenous 11ß-hydroxyglucocorticoids to the mineralocorticoid receptor but also to the glucocorticoid receptor (24); therefore, the absence of an impact of the MR agonist fludrocortisone does not preclude an effect of 11ß-HSD2 inhibition on BP. Indeed, the influence of the modulation of the activity of 11ß-HSD2 on the contractility of aortic preparations or on binding of angiotensin II on vascular smooth-muscle cells appeared to be mediated by both glucocorticoid and mineralocorticoid receptors (12–14).

The administration of GA reduced the plasma potassium concentrations in all subjects. This decline in plasma potassium concentrations was not explained by changes in dietary potassium intake for the following reasons. First, predialytic and postdialytic weight did not change during the study periods. Second, predialytic urea, phosphate, and creatinine concentrations were not affected by the intake of GA. Third, all patients were dialysed for many years, educated by dietitians, and nutritionally compliant with constant predialysis plasma potassium for several months before they entered the study. A decline in plasma potassium of the same magnitude as that observed in this study has been described elsewhere by Singhal et al. (23) in patients undergoing hemodialysis who were given fludrocortisone. Although some of the latter patients investigated were not anuric, it is likely that their loss of potassium was extrarenal (23). The bowel is probably a major source of extrarenal potassium loss in patients with anuria (25). Potassium secretion is a well-established mechanism of rectal and colonic mucosa (26,27). This loss is regulated at least in part by MR and is amiloride sensitive (28). The MR activated driving force is a Na,K-ATPase (26,29). The activation of the MR by fludrocortisone enhances the rectal electrical potential difference, an effect that is mimicked by inhibiting 11ß-HSD2 in segments of normal rectal colon obtained from humans (30).

Our observation of a decreased plasma potassium without substantial sodium retention or increase in BP by GA might be the basis for a potentially useful novel strategy to treat patients undergoing hemodialysis who have a tendency toward increased potassium concentrations. Before this strategy is applied in clinical practice, the effect of aldosterone receptor activation in the heart has to be considered. Sato et al. (31) observed an association between cardiac hypertrophy and aldosterone concentrations in patients undergoing hemodialysis, an effect that is in line with the growth-promoting activity of aldosterone in nonepithelial cells (32). The potential relevance of aldosterone-induced myocardial fibrosis has been demonstrated in the Randomized Aldactone Evaluation Study trial (33). In that trial, the blockade of aldosterone receptors by spironolactone reduced morbidity and mortality in patients with heart failure. Thus, activation of MR by a strategy designed to inhibit 11ß-HSD2 by GA in patients on hemodialysis might be harmful for the heart. On the other hand, our observation that activation of MR decreases plasma potassium concentrations indicates that the administration of spironolactone for the prevention of myocardial fibrosis and heart failure might increase the risk of hyperkalemia in patients on hemodialysis.

In conclusion, this investigation has demonstrated that a decreased 11ß-HSD2 activity does not increase BP in patients on hemodialysis. Furthermore, a pivotal role of extrarenal potassium loss by MR activation is suggested, an observation that might be relevant in a time when the nephrology community is tempted to prescribe spironolactone to patients on hemodialysis.


   Acknowledgments
 
We thank Elisabeth Calame and Claude Jenni for excellent technical assistance. This work was supported by two grants from the Swiss National Foundation for Scientific Research (32-57205.99 and 31-061505.00) and by a grant from the Novartis Foundation for Clinical Research.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication June 12, 2001. Accepted for publication June 23, 2001.




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