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

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.

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.

Eligibility Criteria:
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.)