Vascular Dysfunction in Human Obesity Hypertension
Condition: Obesity; Prehypertension; Hypertension
MeSH terms: Hypertension; Prehypertension; Obesity
Intervention: Clonidine; Hydrochlorothiazide; Placebo
Intervention MeSH terms: Hydrochlorothiazide; Clonidine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 33.0
Sex: All
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Prehypertension; Hypertension; Obese; Sympathetic Nervous System; renin-angiotensin system; Endothelial function

Summary:

      The purpose of the study is to test the effects of blocking sympathetic nerve activity with a
      drug called clonidine on blood vessel function and muscle nerve activity in adults who are
      obese and have high blood pressure.

      The cohort of subjects will consist of 69 healthy young men and women age 18-79 years who are
      obese, defined as a body mass index > or = to 30 kg/m2, who have untreated systolic
      hypertension (systolic blood pressure > or = to 130 - <180 mmHg- average of at least 3
      measurements 2 min apart after 10 min seated resting position). These 69 subjects will then
      be randomized to 3 treatment arms: clonidine (0.1 mg/day), hydrochlorothiazide (25 mg/day) or
      placebo for 4 weeks in years 1 and 2. All tablets will be encapsulated by to look identical.
      Subjects will randomly (1:1:1) receive one of the following combinations in a double-blind,
      placebo-controlled design:

        1. Oral clonidine (0.1 mg twice/day)

        2. Oral hydrochlorothiazide (12.5 mg twice/day)

        3. Oral placebo

      I
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willing and able to provide written, signed informed consent after the nature of the
             study has been explained, and prior to any research-related procedures.

          -  Systolic blood pressure >/= 130 mmHg and <180 mmHg

          -  Age is > or = 18 and < or = 79 years of age

          -  Weight stable (+/- 5 lbs) for the previous 3 months

          -  Healthy, as determined by health history questionnaire, blood chemistries, 12-lead ECG

          -  Blood chemistries indicative of normal renal (creatinine <2.0 mg/dl), liver (<3 times
             upper limit for ALT, AST), and thyroid function (TSH between 0.4 - 5.0 mU/L)

          -  If currently receiving treatment with or taking any of the following supplements, be
             willing and able to discontinue taking them for 2 weeks prior and throughout the
             treatment period: Vitamin C, E or other multivitamins containing vitamin C or E; or
             omega-3 fatty acids.

          -  No history of cardiovascular disease (e.g., heart attack, stroke, heart failure,
             valvular heart disease, cardiomyopathy), Type 1 or Type 2 diabetes, or peripheral
             arterial disease

          -  Non-smokers, defined as no history of smoking or no smoking for at least the past 1
             year

          -  Normal resting 12-lead ECG (no evidence of myocardial infarction, left ventricular
             hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial
             fibrillation/flutter)

        Exclusion Criteria:

          -  Systolic blood pressure >/=180 mmHg or diastolic blood pressure >110 mmHg

          -  History of cardiovascular disease such as heart angioplasty/stent or bypass surgery,
             myocardial infarction, stroke, heart failure with or without left ventricular ejection
             fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart
             transplantation, Type 2 and Type 1 diabetes

          -  Smoking or history of smoking within past one year

          -  History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal
             reflux disease (GERD), or metabolic acidosis

          -  History of chronic obstructive pulmonary disease (COPD)

          -  Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left
             ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial
             fibrillation/flutter)

          -  Serious neurologic disorders including seizures

          -  History of renal failure, dialysis or kidney transplant

          -  Serum creatinine > 2.0 mg/dL, or hepatic enzyme (ALT/AST) concentrations > 3 times the
             upper limit of normal

          -  History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or
             positive HIV, Hepatitis B or C test at screening.

          -  Use of any investigational product or investigational medical device within 30 days
             prior to screening, or requirement for any investigational agent prior to completion
             of all scheduled study assessments.

          -  History of recent chicken pox, shingles or influenza (ie., risk of Reye's syndrome)

          -  Recent flu-like symptoms within the past 2 weeks

          -  Pregnant or breastfeeding at screening, or planning to become pregnant (self or
             partner) at any time during the study. A urinary pregnancy test will be done on all
             females. If test is positive, the subject will be excluded.

          -  Women with history of hormone replacement therapy within the past 6 months

          -  History of rheumatoid arthritis, Grave's disease, systemic lupus erythematosis, and
             Wegener's granulomatosis;

          -  Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin,
             insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents

          -  History of co-morbid condition that would limit life expectancy to < 6 months.

          -  Taking chronic non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,
             indomethacin, naproxen, acetaminophen (Tylenol), ibuprofen (Advil, Motrin) and not
             able or willing to go off of for 2 weeks prior and during the study

          -  Taking cox-2 inhibitors (Celebrex, Vioxx, etc) or allopurinol (Zyloprim, Lopurin,
             Allopurin)

          -  Taking blood thinners such as coumadin (Warfarin), enoxaparin (Lovenox); clopidogrel
             (Plavix); dipyridamole (Persantine); heparin;

          -  Taking diabetic medications (Metformin, glyburide, insulin, etc.), thiazolidinediones
             (Avandia, Rezulin, Actos);

          -  Taking steroids or biologics : corticosteroids (prednisone); methotrexate, infliximab
             (Remicade), etanercept (Enbrel); anakinra;

          -  Taking thyroid medications such as levothyroxine (Levoxyl, Synthroid, Levoxyl,
             Unithroid); Levodopa;

          -  Taking Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or
             Revatio®); PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone); lithium

          -  May participate if no use of the following medications in the 48 hours prior to
             experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil,
             Motrin), other any non-steroidal anti-inflammatory drugs (NSAIDS)

          -  Vulnerable populations (prisoners, etc.)

          -  Any condition that, in the view of the PI, places the subject at high risk of poor
             treatment compliance or of not completing the study.

          -  History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass of
             wine, 1 mixed cocktail containing 1 oz alcohol)

          -  On weight loss drugs (e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim
             (phenylpropanol-amine), or similar over-the-counter medications) within 3 months of
             screening

          -  Any surgery within 30 days of screening