The Role of Mineralocorticoid Receptors in Vascular Function
NCT ID: NCT00759525
Last Updated: 2016-10-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2/PHASE3
15 participants
INTERVENTIONAL
2002-02-28
2009-09-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
QUADRUPLE
Study Groups
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1
Glycyrrhetic Acid
Glycyrrhetic Acid
130 mg daily for fourteen days
2
Placebo
Placebo
Placebo daily for fourteen days
Interventions
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Glycyrrhetic Acid
130 mg daily for fourteen days
Placebo
Placebo daily for fourteen days
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
* Abnormal physical finding
* Blood test values for total and LDL cholesterol, CBC, sodium, potassium, creatinine, and glucose laboratories greater 1.5 times normal
18 Years
85 Years
ALL
Yes
Sponsors
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Brigham and Women's Hospital
OTHER
Responsible Party
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Joshua A. Beckman, MD
Principal Investigator
Principal Investigators
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Joshua A Beckman, MD
Role: PRINCIPAL_INVESTIGATOR
Brigham and Women's Hospital
Locations
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Brigham and Women's Hospital
Boston, Massachusetts, United States
Countries
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References
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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.
Related Links
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Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans.
Other Identifiers
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2001-P-001404
Identifier Type: -
Identifier Source: org_study_id