The Role of Mineralocorticoid Receptors in Vascular Function
Condition: Apparent Mineralocorticoid Excess (AME)
MeSH terms: Mineralocorticoid Excess Syndrome, Apparent; Hyperaldosteronism
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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.
    

Intervention name(s): Glycyrrhetic Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 130 mg daily for fourteen days; Placebo daily for fourteen days
Other intervention name(s): licorice root sweetener
Intervention MeSH terms: Glycyrrhetinic Acid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science