Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal. Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the HyperPATH cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure. The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.
Name: Eplerenone vs AmlodipineDescription: We posit that decreases in striatin activity/levels increases aldosterone secretion resulting in hypertension and salt sensitive blood pressure. Thus, our mechanistic clinical study will assess whether hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the striatin risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure with a secondary outcome of salt sensitive blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.Type: Drug
Epleronone Arm Amlodipine Arm
Description: Subjects will be counseled regarding liberal salt dietary intake to ensure similar intakes in all subjects [Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. After completion of this diet for 7 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center between 7-8 AM, fasting, and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Procedure will be performed before randomization and at the completion of 16 weeks of therapy.Measure: Systolic supine morning liberal salt automated blood pressure Time: Change in blood pressure between baseline and 16 weeks of randomized drug therapy
Description: First step: subjects will ingest a liberal salt intake [Na+ (200 mEq/day)] for 7 days. The subject will come to the study unit between 7-8 AM, fasting. After remaining supine for 60-90 mins, their BP will be measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Second step: subjects will then be fed a restricted salt diet (10 mEq Na+/day) for 7 days. On the morning of the 7th day, the subjects will come fasting to the study unit between 7-8 AM, and the studies performed as detailed above. The BP data from the two diet studies will allow us to calculate SSBP. The procedures will be performed before randomization and at the completion of 16 weeks of therapy.Measure: Systolic salt sensitive blood pressure Time: Change in blood pressure between baseline and 16 weeks of randomized drug therapy
There are 2 SNPs
INCLUSION CRITERIA: 1. rs2540923A allele carrier 2. ages >17 years; 3. hypertension as defined by primary physician; 4. not on more than two anti-hypertensives; 5. normal renal, metabolic, electrolyte, complete blood cell count, and lipid profile laboratory tests; 6. if on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist, needs to be washed out for 3 months.
SUBJECT POPULATION: It is estimated that most of the striatin rs2540923 risk allele carriers will come from our HyperPATH cohort.
Based on our previous studies the investigators estimated that approximately 10% of hypertensives will be carriers of the rs2540923 risk allele.
All subjects will be genotyped at rs2540923, and the risk allele carriers will be entered into the protocol and randomized blindly into one or the other treatment arms.
The subjects evaluated in this protocol are hypertensive and carry the Striatin rs254093 risk allele.