The Effects of Renin Inhibition on Fibrinolytic Balance and Endothelial Function

Qualifying subjects will be withdrawn from RAAS blockers in a stepwise fashion over one to two weeks. All other blood pressure medications will be continued. If the subject's blood pressure rises above SBP \> 170 or DBP \> 120 at any time during the study, they will be excluded and the subject will restart their home medication(s). Week Two - Visit 2 - Post-taper visit: will be issued hydrochlorothiazide (25mg po, qd x 18 weeks, open label). All study medications will be taken daily between 7 and 10 AM. PAI-1 blood sample will be drawn. Pre-menopausal women will schedule this visit for when they have began their cycle. Week Four- Visit 3 - If their BP (\> 120/60 mmHg), potassium (≤ 5.5 meq/dl) and renal function permit (Cr ≤ 1.5 mg/dl), they will be randomized to aliskiren (150 mg po, qd x 2 weeks) or placebo. If applicable, a urine pregnancy test will be done for child bearing age females. Week Six - Visit 4 - Titration visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, and basic metabolic panel. If their BP, potassium and renal function permit, the medication will be increased to aliskiren (300 mg po, qd x 4 weeks) or placebo (double dose). If applicable, a urine pregnancy test will be done for child bearing age females. Week Eight - Visit 5 - Post-Titration visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check and basic metabolic panel. If their BP, potassium and renal function permit, they will remain on the current dose of aliskiren. Week 10 - Visit 6 - Study Day 1 - Patients will be admitted to the GCRC as an inpatient. They will be asked to lie supine for 24 hours with the head of their bed no higher than 10 degrees. They will have an interval history and physical. An IV catheter will be placed. After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone. They will have a baseline BMP, high sensitivity C-Reactive Protein (hsCRP) and CBC. They will have blood drawn every 3 hours for PAI-1 antigen levels, plasma renin activity, plasma ACE activity, plasma aldosterone levels, plasma cortisol and melatonin. White blood cells will be harvested in PaxGene tubes for future extraction of white blood cell mRNA. They will be on a eucaloric, low sodium diet. At the end of the study day they will remain on their home medications, HCTZ (25mg po, qd), however they will stop their current blinded study medication (aliskiren or placebo). Subjects will have DNA banked from unused blood buffy coats. If applicable, UA pregnancy test will be performed by CRC nurses on admission. Washout Period - The reason for the washout period is four-fold. The washout period insures that drug is completely washed out of the system before initiation of placebo in the arm that received aliskiren first. This will allow the study to observe a placebo effect on blood pressure in the "aliskiren first" arm, in the event that there is one. It would also insure that that sufficient time has passed between SD1 and SD 2 to see the effect of placebo on hsCRP in the "aliskerin first" arm. From a safety standpoint, it insures that subjects have more than 8 weeks to recover their blood counts between study days, as a significant amount of blood is drawn on each study day. Fourth, as there is a menstrual variation in Pai-1 levels, it insures that pre-menopausal women participating in the study will be the same phase of their cycle on SD1 and SD2. Week 12 - Visit 7 - Mid-Washout visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check. If their BP permits (\<170/120 mmHg) they will remain off study medication. If they are anemic (Hgb \< 11) they will be started on iron supplementation. Week 16 - Visit 8 - Post-Washout visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, BMP and CBC, if indicated. If BP and renal function permit, the patient will receive their crossover medication (placebo x 2 weeks or aliskiren 150mg po, qd x 2 weeks). If applicable, a urine pregnancy test will be done for child bearing age females. Week 18 - Visit 9 - Titration visit 2: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, and basic metabolic panel, and CBC if indicated. If their BP, potassium and renal function permit, the medication will be increased to aliskiren (300 mg po, qd x 4 weeks) or placebo (double dose). Week 20 - Visit 10 - Post-Titration visit 2: Subjects will return to the GCRC for an interval history, pill count, blood pressure check and basic metabolic pane, and CBC if indicated. If their BP, potassium and renal function permit, they will remain on the current dose of aliskiren. If their Hgb ≥ 11 mg/dl, they will be able to participate in the final study day. Week 22 - Visit 11 - Study Day 2: Patients will be admitted to the GCRC as an inpatient. They will be asked to lie supine for 24 hours with the head of their bed no higher than 10 degrees. They will have an interval history and physical. An IV catheter will be placed. After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone. They will have a baseline BMP, hsCRP, and CBC. They will have blood drawn every 3 hours for PAI-1 antigen levels, plasma renin activity, plasma ACE activity, plasma aldosterone levels, plasma cortisol and melatonin. White blood cells will be harvested in PaxGene tubes for future extraction of white blood cell mRNA. They will be on a eucaloric, low sodium diet. At the end of the study day they will remain on their home medications, and resume home medications that were previously stopped for study purposes. If applicable, UA pregnancy test will be performed by CRC nurses on admission.