(Verbatim from the application): Low-renin hypertension is common in African Americans, with many failing to achieve a normal blood pressure despite the availability of a wide variety of antihypertensive agents. The low-renin state is consistent with increased retention of sodium. We have evidence that blacks have higher overall activity of the epithelial sodium channel (ENaC), a principal site for reabsorption of sodium within the kidney and where certain molecular mutations result in retention of sodium and severe low-renin hypertension (Liddle's syndrome). ENaC is upregulated by aldosterone. In the present proposal, we will study the usefulness of two drugs that inhibit ENaC activity, spironolactone, an antagonist of aldosterone, and amiloride, a direct inhibitor of ENaC, in blacks with low-renin hypertension who have shown resistance to treatment. We will follow a simple protocol wherein we will study patients taking an optimal regimen of antihypertensive medication including a full dose of diuretic but in whom a normal blood pressure has not been achieved. The patients will be randomized to either spironolactone 25 mg per day, amiloride 10 mg per day, the combination of spironolactone 25 mg and amiloride 10 mg per day, or placebo for 9 weeks.
In Specific Aim #1, we will test the hypothesis that drug-resistant, low-renin hypertensive blacks normalize their blood pressure in response to treatment with small doses of agents that reduce ENaC function. We will also test for a synergistic effect of spironolactone with amiloride to lower blood pressure.
In Specific Aim #2, we will test the hypothesis that the mechanism whereby the anti-ENaC drugs lower blood pressure is by reducing an intrinsically higher level of ENaC function, as evidenced by lower levels of renin and aldosterone at baseline and greater increments during treatment in responders.
In Specific Aim #3, we will test the hypothesis that blood pressure responses to spironolactone are related to the presence of molecular variants in ENaC subunits, variants that have been shown previously to associate with level of blood pressure. In summary, we explore unique but simple approaches to treatment of low-renin hypertension in blacks, a treatment modality that could prove useful to many patients currently with uncontrolled blood pressure.
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| Chun, Tae-Yon; Chander, Praveen N; Kim, Jong-Won et al. (2008) Aldosterone, but not angiotensin II, increases profibrotic factors in kidney of adrenalectomized stroke-prone spontaneously hypertensive rats. Am J Physiol Endocrinol Metab 295:E305-12 |
| Chun, Tae-Yon; Pratt, J Howard (2005) Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes. Mol Cell Endocrinol 239:55-61 |
| Saha, Chandan; Eckert, George J; Pratt, J Howard et al. (2005) Onset of overweight during childhood and adolescence in relation to race and sex. J Clin Endocrinol Metab 90:2648-52 |
| Willis, Lynn R; Evan, Andrew P; Connors, Bret A et al. (2005) Shockwave lithotripsy: dose-related effects on renal structure, hemodynamics, and tubular function. J Endourol 19:90-101 |
| Shankar, R Ravi; Eckert, George J; Saha, Chandan et al. (2005) The change in blood pressure during pubertal growth. J Clin Endocrinol Metab 90:163-7 |
| Shankar, R Ravi; Ferrari, Paolo; Dick, Bernard et al. (2005) Activity of 11beta-hydroxysteroid dehydrogenase type 2 in normotensive blacks and whites. Ethn Dis 15:407-10 |
| Chun, Tae-Yon; Pratt, J Howard (2004) Non-genomic effects of aldosterone: new actions and questions. Trends Endocrinol Metab 15:353-4 |
| Palacios, Cristina; Wigertz, Karin; Martin, Berdine R et al. (2004) Sodium retention in black and white female adolescents in response to salt intake. J Clin Endocrinol Metab 89:1858-63 |
| Degawa-Yamauchi, Mikako; Dilts, Jason R; Bovenkerk, Jason E et al. (2003) Lower serum adiponectin levels in African-American boys. Obes Res 11:1384-90 |
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