Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 1

Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 1

The purpose of this study is to test the hypothesis that combined angiotensin receptor blockade (ARB)/neprilysin (NEP) inhibition potentiates the effects of exogenous bradykinin, substance P, and brain natriuretic peptide (BNP) on forearm blood flow or endothelial tissue-type plasminogen activator (t-PA) release compared to ARB alone. A secondary goal is to determine if there is an interactive effect of ARB/NEP inhibition and dipeptidyl peptidase 4 (DPP4) inhibition on responses to these peptides.

After informed consent is obtained, subjects will undergo a screening history and physical exam, and anti-hypertensive medications will be withdrawn. During this period, blood pressure (BP) will be measured every one to three days.

After subjects have been off anti-hypertensive medications for three weeks (four for spironolactone), they will be randomized to four-week treatment with valsartan 160 mg bid (80 mg bid for one week, then 160 mg bid) or LCZ696 200 bid (100 mg bid for one week, then 200 mg bid) in a double-blind fashion. On the morning of the 28th day of study drug, subjects will report to the Vanderbilt Clinical Research Center (CRC) after an overnight fast. Subjects will be studied in the supine position in a temperature-controlled room. They will be instrumented for intra-arterial infusions. Subjects will be given their last dose of study drug. One hour after drug administration, we will measure forearm blood flow (FBF) and give bradykinin, substance P, or BNP. Each peptide will be infused in three graded doses for five minutes. After administration of all three peptides, subjects will be allowed to rest for an hour. Then they will be given a single oral dose of sitagliptin 200 mg and be allowed to rest for 90 minutes. We will repeat baseline measurements and the peptide infusions with an intervening rest period. The four-week study treatment and protocol will be repeated after a three-week washout, until participants complete both arms.

Inclusion Criteria:

1. Patients with essential hypertension defined as having

   1. untreated, seated systolic blood pressure (SBP) of 130 mmHg or greater on three separate occasions, or
   2. untreated, seated diastolic BP (DBP) of 80 or greater on three separate occasions, or
   3. taken anti-hypertensive agent(s) for a minimum of six months.

2. For female subjects, the following conditions must be met:

   1. postmenopausal status for at least one year, or
   2. status post-surgical sterilization, or
   3. if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-human chorionic gonadotropin (hCG) testing prior to drug treatment and on every study day.

Exclusion Criteria:

1. Presence of secondary form of hypertension
2. Symptomatic hypertension and/or SBP>170 mmHg or DBP>110 mmHg, relevant to the washout period
3. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, angiotensin-converting enzyme inhibitor (ACEi), ARBs, or NEPi, as well as known or suspected contraindications to the study drugs
4. History of angioedema
5. History of pancreatitis or known pancreatic lesions
6. History of significant cardiovascular disease (other than essential hypertension and left ventricular hypertrophy)
7. Symptomatic hypotension and/or a SBP<100 mmHg at screening or <95 mmHg during the study
8. Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study
9. Individuals using oral contraceptives and smokers in order to reduce the risk of thrombosis following arterial line placement
10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
11. Presence of significant pulmonary disorders
12. Type 1 diabetes
13. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
14. Hematocrit <35%
15. Impaired renal function [estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)
16. Use of hormone-replacement therapy
17. Breast feeding and pregnancy
18. History or presence of immunological or hematological disorders
19. History of malignancy other than non-melanoma skin cancer
20. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
21. Clinically significant gastrointestinal impairment that could interfere with drug absorption
22. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
23. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs
24. Treatment with chronic systemic glucocorticoid therapy within the last year
25. Treatment with lithium salts
26. History of alcohol or drug abuse
27. Treatment with any investigational drug in the one month preceding the study
28. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
29. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study