The Role of Mineralocorticoid Receptors in Vascular Function

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00759525
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 91
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Apparent Mineralocorticoid Excess (AME)	Drug: Glycyrrhetic Acid; Drug: Placebo	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: The Role of Mineralocorticoid Receptors in Vascular Function
• Study Start Date: Feb 1, 2002
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Forearm Blood Flow [Outcome was measured at the end of each study period (i.e. 14 days after Baseline measurements were taken)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Joshua A. Beckman, MD, Principal Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT00759525
• Other Study ID Numbers: 2001-P-001404
• First Posted: Sep 25, 2008
• Last Update Posted: Oct 26, 2016
• Last Verified: Sep 1, 2016

• Additional relevant MeSH terms: Mineralocorticoid Excess Syndrome, Apparent; Hyperaldosteronism; Glycyrrhetinic Acid

Study Results

Participant Flow

Arm/Group Title	Glycyrrhetinic Acid First, Then Placebo	Placebo First, Then Glycyrrhetinic Acid
Arm/Group Description	Glycyrrhetic Acid-130 mg/day for 14 days followed by placebo	Placebo followed by Glycyrrhetic Acid-130 mg/day for 14 days
Period Title: First Intervention (14 Days)
STARTED	7	8
COMPLETED	7	8
NOT COMPLETED	0	0
Period Title: First Intervention (14 Days)
STARTED	7	8
COMPLETED	7	8
NOT COMPLETED	0	0
Period Title: First Intervention (14 Days)
STARTED	7	8
COMPLETED	7	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27 (7)
Sex: Female, Male (Count of Participants)
Female	7 46.7%
Male	8 53.3%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Forearm Blood Flow
Description	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.
Time Frame	Outcome was measured at the end of each study period (i.e. 14 days after Baseline measurements were taken)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycyrrhinitic Acid	Placebo
Arm/Group Description	All of the 15 subjects received both glycyrrhinitic acid (130mg/day) (GA) for a 14-day period and placebo for a 14-day period. Approximately half of the subjects received GA before placebo; the other half received placebo before GA. There was a 2-week washout period between the two conditions.	All of the 15 subjects received both glycyrrhinitic acid (130mg/day) (GA) for a 14-day period and placebo for a 14-day period. Approximately half of the subjects received GA before placebo; the other half received placebo before GA. There was a 2-week washout period between the two conditions.
Measure Participants	15	15
Mean (Standard Error) [ml/100ml of tissue/min]	1.87 (0.26)	1.34 (0.20)

Adverse Events

Time Frame	30 days.
Adverse Event Reporting Description	Subjects were queried concerning their catheter insertion site.
Arm/Group Title	Glycyrrhetinic Acid First, Then Placebo		Placebo First, Then Glycyrrhetinic Acid
Arm/Group Description	Healthy subjects without medical condition.		Healthy subjects without medical condition.
All Cause Mortality
	Glycyrrhetinic Acid First, Then Placebo		Placebo First, Then Glycyrrhetinic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Glycyrrhetinic Acid First, Then Placebo		Placebo First, Then Glycyrrhetinic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Glycyrrhetinic Acid First, Then Placebo		Placebo First, Then Glycyrrhetinic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.