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

• Status: Active, not recruiting
• Trial end date: 2024-12-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Vanderbilt University Medical Center
• Treatments: Bradykinin; Kininogens; LCZ 696; Neurokinin A; Sacubitril and valsartan sodium hydrate drug combination; Sitagliptin Phosphate; Substance P; Valsartan

Criteria

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