The Role of Mineralocorticoid Receptors in Vascular Function

The purpose of this study is to figure out how decreasing the activity of 11-beta hydroxysteroid dehydrogenase (11-beta HSD) will affect your blood vessel function. 11-beta HSD, which is found in the kidneys and blood vessels, is a natural protein that when active helps to keep your blood pressure under control.

Study Overview

• Status: Completed
• Conditions: Apparent Mineralocorticoid Excess (AME)
• Intervention / Treatment: Drug: Glycyrrhetic Acid; Drug: Placebo

Detailed Description

This study intends to determine whether activation of mineralocorticoid receptors affects vascular function. Vascular function relies on two components of the blood vessel: the inner lining (endothelium) and the vascular smooth muscle. In specific aim 1, we seek to determine if that inhibition of the enzyme 11-beta hydroxysteroid dehydrogenase (11-beta-HSD) will impair endothelium-dependent vasodilation and/or vascular smooth muscle function.

The syndrome of apparent mineralocorticoid excess (AME) is a rare disorder identified in approximately 50 individuals characterized by low-aldosterone hypertension, associated with low renin and hypokalemia These subjects avidly retain salt and water, have suppression of both plasma renin and aldosterone levels, but clinically appear as though they have a state of mineralocorticoid excess. A detailed series of investigations has elucidated the cause of this syndrome: severe attenuation of the enzyme 11 beta-hydroxysteroid dehydrogenase (11-beta-HSD). 11-beta-HSD converts cortisol, able to activate mineralocorticoid receptors to cortisone, which cannot. This abnormality can be identified by measuring an abnormal ratio of urinary breakdown products of cortisol and cortisone. Subjects with AME have a high ratio indicative of elevated cortisol concentrations.

Although classical AME is a rare syndrome with a specific recessive inheritance, several other mutations have been identified which cause a varying severity of disease. Recent evidence has suggested mild abnormalities in this pathway may be much more common. In fact two studies have demonstrated that subjects with essential hypertension had greater levels of cortisol/cortisone urinary levels than matched controls. Thus, mild abnormalities of this enzyme may be an important contributor to a segment of patients with high blood pressure. Further, this is the pathway by which consumption of excess black licorice causes hypertension. Black licorice contains glycyrrhizic acid that selectively inhibits 11 beta-HSD. Glycyrrhizic acid is used as a dietary sweetener and sold in "health-food" stores and may also play a epidemiological role in hypertension.

Analogous to the renin-angiotensin system, 11-beta-HSD is not only found in the kidneys, but is found in both vascular endothelial (inner lining) and smooth muscle cells. Hypertension, similar to other risk factors for cardiovascular disease impairs vascular function. One of its major effects is decreasing the bioavailability of endothelium-derived nitric oxide. Nitric oxide contributes importantly to vascular homeostasis by modulating vascular tone, inhibiting both platelet aggregation and coagulation, and inhibition translocation of leukocytes into the vascular wall. Further, patients with hypertension have increased endothelin-1 production and receptor activation. Endothelin-1 antagonizes the beneficial activities of nitric oxide. Experimentally, inactivation of 11 beta-HSD in a rat model has been demonstrated to cause hypertension, increase endothelin receptor A activation and decrease bioavailability of endothelium-derived nitric oxide. Inhibition of mineralocorticoid receptors in this model prevents impairment of vascular function. Thus, in animal models, abnormalities in this pathway may not only cause hypertension, but create an environment favorable to the development and progression of atherosclerosis. Further, recent evidence suggests that activation of this pathway contributes importantly to the morbidity and mortality in patients with congestive heart failure. A large, randomized study demonstrated that a small dose of a mineralocorticoid inhibitor, spironolactone, substantially reduced morbidity and mortality in patients with severe heart failure. Experimentally, spironolactone improved vascular function in patients with congestive heart failure.

Therefore, we seek to characterize the vascular effects of this pathway in humans. This submission involves one protocol: 1) to determine if reversible inhibition of 11 beta-HSD decreases the bioavailability of endothelium-derived nitric oxide and impairs vascular smooth muscle function.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers

Exclusion Criteria:

• Blood pressure above 140/90
• Abnormal physical finding
• Blood test values for total and LDL cholesterol, CBC, sodium, potassium, creatinine, and glucose laboratories greater 1.5 times normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Placebo	Drug: Placebo; Placebo daily for fourteen days
Active Comparator: 1; Glycyrrhetic Acid	Drug: Glycyrrhetic Acid; 130 mg daily for fourteen days; Other Names: licorice root sweetener

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forearm Blood Flow	At the end of each 14-day intervention (Glycyrrhinitic acid or Placebo), vascular endothelial function was assessed by measuring forearm blood flow and comparing to Baseline. The outcome measure depicted below reflects the change in forearm blood flow from Baseline after completing the glycyrrhinitic acid regimen as well as the change in forearm blood flow from Baseline after taking the matching placebo.	Outcome was measured at the end of each study period (i.e. 14 days after Baseline measurements were taken)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Joshua A Beckman, MD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Sobieszczyk P, Borlaug BA, Gornik HL, Knauft WD, Beckman JA. Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans. Clin Sci (Lond). 2010 Aug 5;119(10):437-42. doi: 10.1042/CS20100087.

Helpful Links

• Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans.

Study record dates

Study Major Dates

• Study Start: February 1, 2002
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: September 24, 2008
• First Submitted That Met QC Criteria: September 24, 2008
• First Posted (Estimate): September 25, 2008

Study Record Updates

• Last Update Posted (Estimate): October 26, 2016
• Last Update Submitted That Met QC Criteria: September 14, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Steroid Metabolism, Inborn Errors; Hyperaldosteronism; Mineralocorticoid Excess Syndrome, Apparent; Anti-Inflammatory Agents; Glycyrrhetinic Acid
• Other Study ID Numbers: 2001-P-001404