MR Antagonist and STRIATIN
MR Antagonist and STRIATIN
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.
HYPOTHESIS:

 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).

 RATIONALE:

 Striatin deficient versus wild-type mice have salt sensitive blood pressure and
 inappropriately increased aldosterone levels on a liberal salt diet. In observational
 studies, the investigators documented that in humans, striatin risk allele carriers also have
 salt sensitive blood pressure. Since aldosterone increases sodium retention, excess
 aldosterone levels could be one mechanism for their salt sensitive blood pressure. The goal
 of this project is to document that a genetic marker identifies individuals who are uniquely
 responsive to mineralocorticoid receptor blockade - personalized, precision medicine. The
 investigators will perform a novel two-limb, proof-of-principle, randomized, double-blind,
 active controlled study contrasting a mineralocorticoid receptor antagonist versus a calcium
 channel blocker in hypertensive striatin risk allele carriers. Our primary outcome will be
 systolic blood pressure assessed on a liberal salt diet with our secondary outcome being salt
 sensitive blood pressure.

 PRELIMINARY RESULTS:

 The investigators recently reported that in two large cohorts from HyperPATH, the striatin
 risk allele carriers have increased blood pressure on a liberal salt diet and salt sensitive
 blood pressure. The link between striatin risk allele and salt sensitive blood pressure was
 seen in ALL participant groups - hypertensives, Caucasians, Africans, males, females, old and
 young. The investigators then created a striatin deficient mouse. It also had salt sensitive
 blood pressure. Furthermore, compared to wild-type mice, the striatin deficient mice had
 increased aldosterone levels on a liberal salt diet. An inappropriate aldosterone level for
 the level of sodium intake is a well-known and important mediator of salt sensitive blood
 pressure and hypertension. Thus, if human striatin risk allele carriers have dysregulated
 aldosterone production, this genetic biomarker could identify subjects at increased risk for
 aldosterone-mediated salt sensitive blood pressure and hypertension.

 SUBJECT POPULATION:

 It is estimated that most of the striatin rs2540923 risk allele carriers will come from our
 HyperPATH cohort. Because there are no racial, age or ethnic differences in the salt
 sensitive blood pressure responses observed, an equal number of females and males and the
 same proportion of Africans as in the HyperPATH cohort will be studied. Additional subjects
 will be recruited from the BWH and Partners Healthcare's Research Patient Data Registry and
 the Partners Biobank. We will use the MGB patient gateway to contact subjects who consented
 to the Research Opportunities Direct to You (RODY) program, which allows researchers to
 contact subjects directly. We will first use the Research Patient Data Registry to obtain an
 identified data set of patients who consented to the RODY program. We will then send a
 recruitment email to those subjects via the patient gateway. We will also use Partners
 Biobank to contact potential study subjects with the striatin rs888083 allele and rs6744560
 allele, as the rs888083 allele and the 6744560 have been genotyped in Partners Biobank.
 Partners Biobank staff will send a re-contact letter, co-signed by the Biobank PI and our PI,
 and an opt-out card to patients. Patients who consent to participate in the Partners Biobank
 provide consent to be re-contacted by the Biobank in the future for additional
 information/samples, and/or to be asked if they would be interested in joining other research
 studies. The Biobank will also provide us with an identified data set that includes patient
 MRNs, names, phone numbers and mailing addresses for all re-contacted patients. Ten business
 days after the Biobank sends the recontact letters to patients, we will call each patient on
 the list (who did not send us the opt-out card) to ask whether they would like to participate
 in our study. As an example of the richness of these sources, Research Patient Data Registry
 contains over 90,000 hypertensive patients, ages 18-65 years with 13.5 % of African descent
 and 52.8 % women. Partners Biobank contains over 14,000 hypertensive subjects between the
 ages of 18-65. We will recruit approximately 105 individuals to have 45 individuals in each
 drug group for analyses, so we aim to enroll approximately 1000 individuals who will be
 consented into the study. This assumes that we will have 90% individuals ineligible due to
 status as a non striatin risk allele carrier, and of those who are allele carriers will have
 10-15% non-completers. Based on our previous studies we estimated that approximately 10% of
 hypertensives will be carriers of the rs2540923 risk allele. We have DNA, history, screening
 laboratory tests, and physical examinations on 4000 individuals in HyperPATH. Approximately
 60% have hypertension and 10% carry the risk allele, i.e., approximately 250 individuals. We
 estimate from our previous use of this cohort that we will be able to recruit 75-80
 individuals during the 4 years of this project. Thus, we will need to recruit 25-30 new
 subjects over four years, i.e., 6-8 per year. The research Patient Data Registry is the
 source from which we have the most success. Approximately 20% of those to whom we send
 requests to participate in the study enter the electronic screening phase. Approximately 50%
 of these subjects enter the clinic screening phase and about 25% of them are enrolled in a
 study that is comparable or more time consuming than the one proposed in this project. Thus,
 we will need to invite each month approximately 200 of the 90,000 hypertensives in the
 Research Patient Data Registry to participate in our study. 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.

 PROTOCOL:

 1. The screened, eligible hypertensives will enter a two to three-week single blind placebo
 washout phase. Pill count will be used to determine compliance. Those with blood
 pressure between 145-170/90-109 mmHg and pill count between 80-100% after two to
 three-weeks will enter the randomized phase and counseled regarding salt intake.

 2. The first step: subjects will be fed a 10 mEq Na+, 100 mEq K+ calculated diet for 6
 days. The meals will be provided by the CCI Dietary Core. On the 7th day, the subjects
 will come to the CCI Ambulatory Clinical Center. After remaining supine for 60-90
 minutes, the subjects will have blood samples obtained for future analyses and their
 blood pressure measured using an automatic recording sphygmomanometer (Space Labs,
 Snoqualmie, WA). Readings will be obtained every 2 minutes for 20 minutes 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
 sodium as a check on balance and stored for future analyses.

 3. The second step: Subjects will be counseled regarding liberal salt dietary intake.
 Subjects will be given high salt broth packets, calcium tablets (as calcium
 bicarbonate), and potassium tablets (as potassium bicarbonate) to supplement their diet
 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. On the morning of the 6th day the
 subject will begin a 24-hour blood pressure recording, using a blood pressure machine
 provided by study staff. After completion of this diet for 6 days, the subject will come
 to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center 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 (Space Labs,
 Snoqualmie, WA). 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. The BP data from 2) and 3) will allow
 us to calculate SSBP, an approach performed successfully more than 500 times in the
 HyperPATH cohort.

 4. The hypertensive striatin risk carrier subjects will be randomized, double blinded to
 one of two primary treatment groups and titrated to effect every four weeks, as was
 previously reported (1, 2), eplerenone 50, 100 and 200 mg daily or amlodipine 2.5, 5 and
 10 mg daily. Study duration will be sixteen weeks.

 5. Participants will be randomized in blocks of four to 1 of 2 study drugs (amlodipine and
 eplerenone). The drug class assignment will remain the same throughout the study for
 each subject. The PI or Co-PI will notify The Brigham and Womens Hospital
 Investigational Drug Pharmacy Service to escalate or maintain current dose on each of
 the two visits. The Brigham and Womens Hospital Investigational Drug Pharmacy Service
 will be responsible for the randomization schema, recording of study drug assignment,
 and dispensing of prescriptions. All others (PI, Co-PI, research staff, subject) will be
 blinded as to drug assignment.

 6. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored
 by study staff weekly as a safety check with the information provided to the study staff
 by email or phone. The blood pressure results from the 7 days prior to the next visit
 will be averaged, with the highest and lowest values discarded. This average blood
 pressure value will be used to determine if the drug dose will be titrated after the
 next visit If the subject has reached goal blood pressure (less than or equal to140/90
 mmHg), then the subject is maintained on his/her current dose. If not, the subject's
 dose is up titrated as per protocol. A member of the research team will contact the
 subject if the blood pressure data are not received within 24-hr of the designated time.
 If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24
 hours apart, or the subject develops cardiovascular symptoms, the subject will be
 terminated from the study and re-started on medications used before the washout period.
 The subject's physician will be contacted.

 7. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly
 during the study. This will be obtained at the time of their monthly visit unless a dose
 increase is made at the time of the visit. Then, the Serum K+ will be obtain one week
 later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart,
 the subject will be terminated from the study. If unexpected adverse event is noted The
 Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so
 as to break code and identify agent.

 8. At the end of four weeks since randomization and the subjects have completed the first
 dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of
 sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive
 supplementary high salt broth packets to ensure that they are reaching the target Na+
 intake. After completion of this diet for 6 days, the subject returns to Center for
 Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90
 minutes again will have blood samples obtained for future analyses and their blood
 pressure measured using an automatic recording sphygmomanometer. Readings will be
 obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and
 the rest averaged. This measurement will be used to assess the blood pressure response
 to a single dose of each agent. From the morning of the 6th to the morning of the 7th
 day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance
 and stored for future analyses.

 9. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored
 by study staff weekly as a safety check with the information provided to the study staff
 by email or phone. The blood pressure results from the 7 days prior to the next visit
 will be averaged, with the highest and lowest values discarded. This average blood
 pressure value will be used to determine if the drug dose will be titrated after the
 next visit If the subject has reached goal blood pressure (less than or equal to140/90
 mmHg), then the subject is maintained on his/her current dose. If not, the subject's
 dose is up titrated as per protocol. A member of the research team will contact the
 subject if the blood pressure data are not received within 24-hr of the designated time.
 If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24
 hours apart, or the subject develops cardiovascular symptoms, the subject will be
 terminated from the study and re-started on medications used before the washout period.
 The subject's physician will be contacted.

 10. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly
 during the study. This will be obtained at the time of their monthly visit unless a dose
 increase is made at the time of the visit. Then, the Serum K+ will be obtain one week
 later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart,
 the subject will be terminated from the study. If unexpected adverse event is noted The
 Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so
 as to break code and identify agent.

 11. At the end of eight weeks since randomization and the subjects have completed the second
 dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of
 sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive
 supplementary high salt broth packets to ensure that they are reaching the target Na+
 intake. After completion of this diet for 6 days, the subject returns to Center for
 Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90
 minutes again will have blood samples obtained for future analyses and will have their
 blood pressure measured using an automatic recording sphygmomanometer. Readings will be
 obtained every 2 minutes for 20 minutes 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 sodium as a check on balance and stored for
 future analyses.

 12. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored
 by study staff weekly as a safety check with the information provided to the study staff
 by email or phone. A member of the research team will contact the subject if the blood
 pressure data are not received within 24-hr of the designated time. If the cuff blood
 pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or
 the subject develops cardiovascular symptoms, the subject will be terminated from the
 study and re-started on medications used before the washout period. The subject's
 physician will be contacted.

 13. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly
 during the study. This will be obtained at the time of their monthly visit unless a dose
 increase is made at the time of the visit. Then, the Serum K+ will be obtain one week
 later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart,
 the subject will be terminated from the study. If unexpected adverse event is noted The
 Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so
 as to break code and identify agent.

 14. At the end of the study, twelve weeks after randomization, subjects will be counseled
 regarding liberal salt dietary intake. Subjects will be given high salt broth packets,
 calcium tablets (as calcium bicarbonate), and potassium tablets (as potassium
 bicarbonate) to supplement their diet 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. On the
 morning of the 6th day the subject will begin a 24-hour blood pressure recording, using
 a blood pressure machine provided by study staff. After completion of this diet for 6
 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory
 Clinical Center 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 (Space Labs, Snoqualmie, WA). 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.

 15. The subject then will have completed the study and will be re-started on medications
 used before the washout period. The subject's physician will be contacted.

 ANTICIPATED RESULTS:

 Based on our Preliminary Results, the investigators anticipate that: 1) in response to the
 first dose of each agent, the risk allele carriers will have significantly greater BP
 reductions with eplerenone than with amlodipine; 2) a significantly lower dose of eplerenone
 will be required to achieve goal BP than with amlodipine; and 3) greater reduction in SSBP
 will occur with eplerenone than with amlodipine. If proven, these results will support: a)
 proof of principle that an activated MR, likely secondary to increased ALDO, is contributing
 to the HTN in STRN risk allele carriers, a conclusion inferred from HET-KO studies described
 in our Preliminary Results; b) that genotype can be used to predict therapeutic response in
 HTN -a positive application of pharmacogenetics to a complex, common condition; and c)
 provide specific information necessary to appropriately statically power and design a
 definitive clinical trial. The investigators also will draw on data obtained from the studies
 performed in AIMS 2 and 3 in designing this new trial. The investigators anticipate that this
 new treatment trial will contrast not only BP and SSBP responses to specific treatments in
 carriers versus non-carriers (a control group) of the STRN risk allele, but also will assess
 the human relevance of the likely mechanisms linking STRN to SSBP, as will be suggested by
 the data generated in the mechanistic studies (AIMS 2 and 3 of this project). For example, if
 AIM 3 shows that STRN deficiency results in decreased RBF response to a liberal salt intake,
 then in addition to measuring the response of BP and SSBP to specific therapy, the
 investigators will measure the treatment's effect on RBF.

 ALTERNATIVE RESULTS AND POTENTIAL PITFALLS:

 First, a negative outcome may not be a true treatment failure, but secondary to: 1) the
 length of treatment being too short; 2) an ALDO mediated effect not blocked by eplerenone; or
 3) an ALDO mediated effect whose mechanism is made worse by blocking the MR. These
 possibilities, in part will be addressed in AIM 2 where the investigators are determining the
 mechanism(s) underlying the STRN/ALDO interaction. Second, a positive outcome could indicate
 that an activated MR is a proximate mediator of the increased liberal salt BP and SSBP
 associated with STRN's risk allele carriers. However, since the investigators did not include
 a control group (non-risk allele carriers), a future study would need to be performed as
 outlined in the Anticipated Results above. Third, the STRN risk allele carriers do have
 increased liberal salt BP and SSBP but the primary mechanism is dysfunction in the renal
 vasculature. This possibility will be addressed in AIM 3. Fourth, the study's length could
 lead to a false positive, i.e. the length is not long enough to see an initial difference
 disappearing with longer therapeutic exposure. However, the investigators believe the trial
 length is appropriate because: 1) most clinical trials using these agents achieve stable BP
 responses during this time interval; 2) with eplerenone treatment, BP nadirs after three
 months with no significant changes even if therapy is extended to a year. Finally, the study
 is too complicated. The investigators will have too many dropouts. The investigators have
 completed this and even more complicated studies in more than 1000 subjects and achieved the
 completion rate assumed for this study.
The subjects evaluated in this protocol are hypertensive and carry the Striatin rs254093
 risk allele or both Striatin rs888083 and rs6744560 risk alleles. Most will be recruited
 from the HyperPATH cohort. The HyperPATH cohort was developed under a SCOR in Hypertension
 program. This program has demographic data and DNA on more than 4000 subjects. Currently,
 nearly 2000 of them have undergone an extensive phenotyping protocol. All hypertensive
 medications have been stopped for 4 weeks before study except agents that interfere with
 the renin-angiotensin-aldosterone system (RAAS) are stopped for three months and amlodipine
 and/or hydrochlorothiazide is added if necessary for blood pressure control until one month
 before study initiation. Then each subject is studied twice on a diet consisting of 100
 mmol potassium, 800 mg calcium, isocaloric, 2500 ml. The two times they are studied are
 after one week of a liberal sodium diet (200 mmol) and after one week of a low sodium diet
 (10 mmol). Blood is obtained supine, upright and after a 3 ng Ang II infusion and a
 norepinephrine dose response curve. BP and renal plasma flow are assessed in response to
 the diet and the Ang II infusion and 24 hour urines are collected on each diet. An oral
 glucose tolerance test is performed on each subject and blood is obtained for DNA. In
 addition to hypertensives, the nearly 2000 intensively studied cohort consists of 75
 individuals in 10 families, 225 sibling pairs with hypertension, 525 normotensive
 individuals without a family history of hypertension or diabetes before the age of 60, and
 250 type II diabetic subjects with or without hypertension. On most of the 4000 subjects
 serum, plasma, urine and DNA is available for measurements and analyses. Currently the data
 set consists of approximately 2100 data points of demographic data, family history,
 biomarkers, and genotypes. The subjects have been recruited from Boston MA, Salt Lake City
 UT, Paris France, Rome Italy and Nashville TN. The demographics consists of the following:
 52% male, 18% of African descent, 3% Asian descent, age 17-66, hypertension stage 1-2, diet
 or oral medication controlled diabetes (80% of the total diabetics). A few subjects will be
 recruited from advertisements on the Internet and in local newspapers, from fliers and
 postings in the hospital, through mailings to households located in the Boston areas and
 through patient registries at Brigham and Womens Hospital. As an example of the richness of
 these sources is the Research Patient Data Registry (RPDR). RPDR is a centralized clinical
 data registry of 2.8 million Brigham and Womens Hospital and Massachusetts General Hospital
 patients. With approval of the Institutional Review Board, investigators may use the RPDR
 Data Acquisition Engine to obtain medical record information for patients with a specific
 diagnosis. Patients who meet inclusion criteria for a specific study can be identified.
 Potential research subjects may be contacted by his/her physician to inform the patient of
 the possibility of participating in a research study and to provide the patient with the
 information for contacting the study personnel. Investigators from Brigham and Womens
 Hospital may apply to use the RPDR. RPDR contains over 90,000 hypertensives, ages 17-65
 years with 13.5 % of African descent and 52.8 % women.

 We reported in our studies using the HyperPATH cohort that there was no racial, age or
 ethnic differences in the salt sensitive blood pressure responses related to Striatin
 allele variants. Thus, an equal number of females and males and the same proportion of
 Africans as in the HyperPATH cohort will be studied. Subjects in HyperPATH and those
 recruited for the new study in this project will have the similar characteristics. The
 range in age is >17; however, it is anticipated that the clear majority will be between the
 ages of 40 and 60 years.

 Hypertensive patients previously treated will be weaned off medications for two-four weeks
 except agents that interfere with the renin-angiotensin-aldosterone system (RAAS) are
 stopped for three months and amlodipine and/or hydrochlorothiazide is added if necessary
 for blood pressure control until one month before study initiation. Thus, these subjects
 will match the characteristics of subjects recruited in HyperPATH. They must have a
 diastolic blood pressure between 95 and 105 mm Hg off medication in each of three screening
 visits. Subjects with diastolic blood pressures greater than 105 mm Hg or systolic blood
 pressures greater than 180 mm Hg will be excluded. Subjects with only elevated systolic
 blood pressure (but diastolic less than 95 mm Hg) will be excluded because such subjects
 were not in the HyperPATH cohort.

 Based on individual statements, subjects with current excessive alcohol use (greater than
 12 oz/ETOH/week) or recreational drug use will be excluded. Subjects taking other
 medications (except thyroid supplements) or weighing more than 150% of an ideal body weight
 will be excluded. Subjects with other major cardiovascular diseases, diabetes, asthma, or
 other major medical illness will be excluded. Subjects who smoke will be excluded. In
 addition, subjects must have normal values for the following screening tests: CBC, serum
 electrolytes, liver enzymes, TSH, urinalysis, 24-hour urine excretion of catecholamines and
 cortisol, and ECG. Specifically, estimated GFR must be > 60 ml/min and serum potassium <
 5.0 mmol/l. Subjects with hypokalemia while on diuretics will be evaluated for
 hyperaldosteronism before inclusion in this study. Cushings syndrome will be ruled out
 clinically, and with a 24-hour urine cortisol if there is clinical uncertainty. For the
 more difficult question of renal artery stenosis, we will perform renal artery digital
 subtraction angiogram in patients with hypertension and a two-component abdominal bruit.
 Patients with greater than 50% renal artery stenosis will be further evaluated, but
 excluded from this study. Subjects with a known sensitivity to any of the agents, such as
 amlodipine or eplerenone will be excluded. Women who are pregnant will be excluded and will
 be dropped from the study if they become pregnant during the study because eplerenone has
 not been approved for use in pregnancy and the activity of the RAAS is dramatically altered
 by pregnancy.

 The screened, eligible hypertensives will enter a two-week single blind placebo washout
 phase. Pill count will be used to determine compliance. Those with BP between
 145-170/90-109 mmHg and pill count between 80-100% will enter the randomized phase,
 counseled regarding salt intake, and randomized double blindly into one of our two
 treatment arms. We will recruit approximately 105 individuals to have 45 individuals in
 each drug group for analyses. This assumes that we will have 10-15% non-completers.

 INCLUSION CRITERIA:

 1. rs2540923A allele carrier OR both Striatin rs888083 and rs6744560 risk 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.

 EXCLUSION CRITERIA:

 1. known cardiac disease other than hypertension

 2. renal, circulatory or neurologic diseases

 3. diabetes; smoking

 4. secondary hypertension as indicated by history, physical examination or screening
 blood and urine tests; any drug therapy, except for anti-hypertensives and replacement
 thyroid medication.