H2SPharm: Peripheral Vascular Effects of Sulfhydryl-containing Antihypertensive Pharmacotherapy on Microvessels in Humans

Sponsor

Penn State University (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT03179163

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Location

Arms

77.4

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

High blood pressure can cause physical changes to the blood vessels of the body (remodeling). If a person who has high blood pressure also has a lot of blood vessel remodeling with their condition, they are more likely to have poor results with medical treatment for hypertension. The researchers examine the impact of different classes of drugs that doctors use to treat high blood pressure (hypertension) on blood vessel remodeling. Some drugs that doctors prescribe for their patients contain a "sulfhydryl group" (a sulfur atom bonded to a hydrogen atom). Drugs that have the sulfhydryl group may reduce blood vessel remodeling more that drugs that do not. For this study, participants who have high blood pressure perform the experiments, take a drug for 16-weeks to lower blood pressure, and repeat the experiments. The researchers randomly assign one of three drugs to participants who have high blood pressure: a diuretic ("water pill"), a drug containing a sulfhydryl (SH) group, or a drug that does not contain a sulfhydryl group. Participants who do not have high blood pressure perform the experiments, but do not take any of the drugs. In some of our experiments, the researchers use a technique called "microdialysis" (MD). With MD, the researchers perfuse some research drugs into the skin on the forearm through tiny tubing that mimics capillaries. These MD drugs mimic or block substances the body naturally makes to control the small blood vessels in the skin. The drugs remain in nickel-sized areas around the tubing and do not go into the rest of the body. The researchers also analyze very small skin samples (skin biopsy) obtained from the forearm. Lastly, the researchers use a standard technique called "flow mediated dilation" (FMD) that uses blood pressure cuffs and ultrasound to look at the health of larger blood vessels in the body. FMD includes placing a small tablet of nitroglycerin under the tongue during part of the test.

Condition or Disease	Intervention/Treatment	Phase
Hypertension,Essential	Drug: Captopril Pill Drug: Enalapril Pill Drug: Hydrochlorothiazide	Phase 1/Phase 2

Detailed Description

Upon initial screening and again within a week of testing, all subjects will have an assessment of 24-hour ambulatory blood pressure. Subject screening will be performed by the Penn State Clinical Translational Research Center (CTRC) medical staff and will include a physical exam by a clinician, anthropometry, and a chemical and lipid profile, liver and renal function. Women will be either postmenopausal (absence of menstruation of >1 year and Follicle Stimulating Hormone (FSH) >25 milli-international units per milliliter (mlU/ml)) and not be taking hormone replacement therapy, or normally menstruating and tested in the early follicular phase of their cycle. Subjects will also go through an assessment of conduit vessel endothelial and vascular smooth muscle function with brachial artery flow-mediated vasodilation (FMD), and sublingual nitroglycerin.

Subjects will undergo initial microdialysis experiments and biopsy samples will be obtained. Subjects will then be randomly assigned to treatment group. Blood pressure will be monitored every 2 weeks and weekly compliance checks will be made by the researcher's nurse coordinator. 24-hour ambulatory blood pressure monitoring will be conducted monthly to determine the efficacy of antihypertensive treatment and to inform dosing titration. Examining pharmacokinetic and dynamic data from the literature indicate that blood pressure lowing and peripheral vascular effects are maximized by 12 weeks of antihypertensive therapy and maintained thereafter. After 16 weeks of the assigned intervention, subjects will repeat microdialysis experiments and additional cutaneous biopsy samples will be obtained. Conduit artery measures including brachial artery FMD and responsiveness to sublingual nitroglycerin will also be evaluated at this time.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

46 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Subjects are grouped as normal (<120/80 mmHg) and hypertensive (≥140/90 mmHg and <160/110 mmHg). All subjects undergo one round of experiments. Hypertensive subjects received randomly-assigned antihypertension medication (ACEi+SH, ACEi, or diuretic) for 16 weeks and then repeat experiments. Normotensive subjects receive no intervention and repeat experiments16 weeks after initial experiments as a time control.Subjects are grouped as normal (<120/80 mmHg) and hypertensive (≥140/90 mmHg and <160/110 mmHg). All subjects undergo one round of experiments. Hypertensive subjects received randomly-assigned antihypertension medication (ACEi+SH, ACEi, or diuretic) for 16 weeks and then repeat experiments. Normotensive subjects receive no intervention and repeat experiments16 weeks after initial experiments as a time control.

Masking:

Double (Investigator, Outcomes Assessor)

Masking Description:

Investigator and Outcomes Assessor are masked according to treatment.

Primary Purpose:

Basic Science

Official Title:

Peripheral Vascular Effects of Sulfhydryl-containing Antihypertensive Pharmacotherapy on Microvascular Function and Vessel Remodeling in Hypertensive Humans

Actual Study Start Date :

Jul 20, 2016

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Normotensive Blood Pressure <120/80 mmHg
Experimental: Hypertensive - ACEi +SH Captopril Pill intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg	Drug: Captopril Pill ACEi+SH Other Names: National Drug Code (NDC) # 00781-8061-01
Experimental: Hypertensive - ACE inhibitor (ACEi) Enalapril Pill intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg	Drug: Enalapril Pill ACEi Other Names: NDC# 51672-4039-03
Active Comparator: Hypertensive - Diuretic Hydrochlorothiazide intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg	Drug: Hydrochlorothiazide diuretic Other Names: NDC# 00603-3857-32

Outcome Measures

Primary Outcome Measures

laser Doppler blood flow [16 weeks]
This measurement is performed using a laser Doppler flow meter. The flow meter produces a non-invasive qualitative and dimensionless index of blood flow in blood vessels.

Secondary Outcome Measures

Systolic Blood Pressure [16 Weeks]
Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The peak blood pressure during a cardiac cycle when the heart contracts.
Diastolic Blood Pressure [16 Weeks]
Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The lowest blood pressure during a cardiac cycle when the heart is between beats.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Women and men
40-65 years
Blood pressure: Normotensive <120/80 mmHg Hypertensive ≥140/90 mmHg and <160/110 mmHg
HbA1C of <6.5%
Women are post-menopausal and not taking hormone replacement therapy, or have normal cycles and are tested in the early follicular phase
Subjects may or may not be taking one doctor-prescribed drug to lower blood pressure (e.g. diuretic, ACE inhibitor).
Must be able to stop physician-prescribed antihypertensive drug for the duration of the subject's participation in the study (with the approval of their personal physician).

Exclusion Criteria:

Relevant to all subjects:

current medications which could conceivably alter the cardiovascular or thermoregulatory control or responses (e.g. beta blockers, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers)
taking a diuretic (also see below)
allergy to test substances
allergy to latex
nicotine use (smoking, chewing tobacco, etc.)
illegal/recreational drug use
pregnancy or breastfeeding
diabetes

Relevant to hypertensive subjects only:

contraindication for all three pharmacotherapy drugs used in this study

o Note: Subjects who have a contraindication (e.g. a condition, medication with a known interaction, known allergy) to only one or two of the three pharmacotherapy drugs, may be assigned one of the pharmacotherapy drugs that is not contraindicated.

history of having taken an ACE inhibitor with antioxidant properties (e.g. Captopril, Zofenopril)
kidney problems
liver problems
history of heart disease or failure
history of blood clots or stroke
angioedema
electrolyte imbalance
planned surgery requiring general anesthesia during the pharmacotherapy period
peripheral vascular disease
diuretics (a subject taking only a diuretic to control the subject's hypertension may be included in the study if the subject stops taking the diuretic for the duration of the subject's participation in the study with the approval of the subject's personal physician.)