The Role of Mineralocorticoid Receptors in Vascular Function

This study has been completed.
Sponsor:
Information provided by:
Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT00759525
First received: September 24, 2008
Last updated: October 16, 2009
Last verified: October 2009
  Purpose

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.


Condition Intervention Phase
Apparent Mineralocorticoid Excess (AME)
Drug: Glycyrrhetic Acid
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Role of Mineralocorticoid Receptors in Vascular Function

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • To determine that inhibition of the enzyme 11-beta hydroxysteroid dehydrogenase (11-beta-HSD) will impair vascular smooth muscle function and endothelial function [ Time Frame: one testing visit every month for 2 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: February 2002
Study Completion Date: September 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Glycyrrhetic Acid
Drug: Glycyrrhetic Acid
130 mg daily for fourteen days
Other Name: licorice root sweetener
Placebo Comparator: 2
Placebo
Drug: Placebo
Placebo daily for fourteen days

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00759525

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Principal Investigator: Joshua A Beckman, MD Brigham and Women's Hospital
  More Information

No publications provided

Responsible Party: Joshua A. Beckman, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00759525     History of Changes
Other Study ID Numbers: 2001-P-001404
Study First Received: September 24, 2008
Last Updated: October 16, 2009
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Mineralocorticoid Excess Syndrome, Apparent
Steroid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Glycyrrhetinic Acid
Mineralocorticoids
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014