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Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 1 | Clinical Trials | Clareo Health

TERMINATEDPHASE4

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

NCT03738878•Vanderbilt University Medical Center

Summary

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.

Detailed Description

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is obtained, subjects will undergo a screening history and physical exam, and anti-hypertensive medications will be withdrawn.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.

Eligibility

Age

18 - 60 years

Sex

ALL

Healthy Volunteers

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
+19 more criteria

Locations (1)

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Key Dates

Start Date

November 15, 2018

Primary Completion Date

December 1, 2024

Completion Date

December 1, 2024

Last Updated

August 3, 2025

Enrollment

ACTUAL participants

Conditions

Hypertension

Interventions

Valsartan

DRUG

LCZ696

DRUG

Bradykinin

DRUG

Substance P

DRUG

BNP

DRUG

Sitagliptin

DRUG

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: August 3, 2025Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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

Inclusion Criteria

Exclusion Criteria

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