Hypertension Clinical Trial
Official title:
ENaC as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes
The purpose of this study is to determine with the administration of amiloride, observe an enhanced natriuresis, reduction in blood pressure and weight compared to the administration of hydrochlorothiazide in Type 2 Diabetics.
Renal sodium retention and extracellular fluid volume expansion are hallmarks of nephrotic
syndrome. There is abundant evidence that this occurs even in the absence of activation of
hormones that are known to activate renal Na transporters. Proteinuria not only reflects
glomerular damage, but also functions as a risk factor for cardiovascular disease, stroke,
end stage renal disease and is associated with extracellular volume expansion and high BP.
In the natural course of Type II diabetes, microalbuminuria and elevations in blood pressure
are thought to occur at around the same time. Blood pressure in microalbuminuric diabetics is
more sensitive to dietary salt intake than in normoalbuminuric patients despite both groups
having similar aldosterone and plasma renin activity levels. Proteolytic processing of ENaC
subunits might provide the primary defect in renal sodium handling in these microalbuminuric
individuals. However, proteinuria is not consistently identified as a risk factor for
incipient elevation in blood pressure and in some studies elevated blood pressure predicts
the advent of microalbuminuria.
Analyses of normotensive normoalbuminuric subjects in previous studies have found that higher
urinary albumin levels in the normal range predicted incident hypertension. A similar finding
was seen in a non-diabetic cohort. These studies suggest that these disparate results may be
related to the cut off that defined microalbuminuria. Another possible explanation is that an
ENaC activator, like plasmin, contributes to the generation of incident hypertension in some
individuals. Levels of albuminuria may not necessarily be reflective of ENaC activator levels
and may vary from individual to individual. Perhaps urinary plasmin and plasminogen provides
a more robust biomarker for those individuals who may develop hypertension.
Recent evidence suggests that in some individuals with glomerular damage, proteases not
normally found in urine enter the urinary space and aberrantly cleave ENaC. In this setting,
filtered plasminogen (inactive precursor) is converted to plasmin (active protease) by
urokinase that is expressed in tubular epithelial lumen. The proteolytic activation of ENaC
would generate a primary defect in renal sodium handling, a mechanism that may be a
particularly important factor leading to increases in extracellular fluid volume and BP that
accompany nephrotic syndrome.
While previous studies have examined the role of amiloride in low-renin hypertension, and as
an additional agent the conventional treatment of hypertension, no human trials have tested
whether ENaC inhibitors impact blood pressure and volume status in the setting of
proteinuria. Over a ten year period, millions of diabetics, 5.3% of Type II diabetics and 28%
of Type I diabetics develop macroscopic proteinuria.
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