Apparent Mineralocorticoid Excess (AME) Clinical Trial
Official title:
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.
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.
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Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science