Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine if Nebivolol improves microvascular perfusion in
      skeletal muscle during exercise in hypertensive patients and whether this improvement is
      accompanied by reduction in vascular oxidative stress or increased endothelial nitric oxide
      synthase (eNOS) expression in humans.
    

Detailed description: 
      In 32 untreated stage 1 hypertensive subjects, the investigators will measure blood pressure;
      noninvasive cardiac output by thoracic electrical bioimpedance (Bioz, Cardio Dynamics);
      forearm mediated vasodilation (FMD), which is a non-invasive assessment of endothelial
      function; collect venous endothelial cells; and measure microvascular perfusion using an
      Octafluoropropane microbubble contrast agent (Definity).

      To obtain FMD, the brachial artery will be imaged using ultrasound. After a clear picture has
      been obtained, the cuff on the same arm will be inflated until it is tight for five minutes.
      During and following this, the subject's arm will continue to be imaged to monitor maximal
      increase in the brachial artery diameter.

      To collect endothelial cells, a thin wire will be inserted in the vein to collect cells from
      the inner lining of the vein. The cells collected will be processed and stained for several
      proteins involved in endothelial cell function, using immunofluorescent technique.

      To assess the microvascular perfusion in the skeletal muscle, a contrast agent (Definity)
      will be administered at baseline and after 5 minutes of rhythmic hand grip exercise at 30% of
      maximal voluntary contraction.

      The investigators will then randomize our subjects to receive 12 weeks of Metoprolol or
      Nebivolol, using a cross over design. There will be a 4 week washout period between the two
      treatments. During the washout period, subjects will be followed after 2 weeks of drug
      withdrawal. Subjects found to have BP > 140/90 mmHg then, will be started on
      hydrochlorothiazide (HCTZ) at 25 mg once daily. Then subjects will be asked to return in 2
      weeks. At that time HCTZ will be stopped if started in the earlier visit, and subject will be
      switched to the remaining treatment (Nebivolol or Metoprolol). Then, the investigators will
      assess microvascular perfusion in the skeletal muscle at rest and during handgrip exercise,
      endothelial function (FMD), and changes in endothelial cell protein expression after 12 weeks
      of Nebivolol and after 12 weeks of Metoprolol treatment in the same subjects.
    

Intervention name(s): Metoprolol succinate; Nebivolol; Non-invasive measurement of Cardiac Output (CO); Endothelial cell collection; Microvascular perfusion assessment using Definity
Intervention type(s): Drug; Drug; Procedure; Procedure; Procedure
Intervention description(s): The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.; The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.; Cardiac Output (CO) will be measured non-invasively at rest and during exercise by thoracic electrical bioimpedance. Stroke volume will be derived from change in impedance/time measured during electrical systole. Cardiac output will be determined as the product of stroke volume and heart rate.; We will collect endothelial cells from a superficial vein, usually in the arm. Following insertion of a peripheral intravenous (IV) catheter, we will collect cells from the inner lining of the vein using a thin, flexible J-tipped wire. The wire will be inserted through the IV into the vein and then removed, along with a sampling of endothelial cells. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.; Using high-resolution ultrasound, we will measure skeletal muscle blood flow during infusion of a solution containing the octafluoropropane microbubble contrast agent, Definity. The solution will be a dilution of 1 vial of Definity to 30 cc of normal saline. The ultrasound probe will be placed over the forearm to obtain images while octafluoropropane microbubbles (Definity) are infused intravenously at the rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit. The microvascular perfusion assessment using Definity be performed at rest as well as during slow and fast handgrip exercises.
Other intervention name(s): Toprol XL; Bystolic; Cardiac output by thoracic electrical bioimpedance; Bioz, Cardio Dynamics International Corporation; Endocell collection
Intervention MeSH terms: Metoprolol; Nebivolol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: hypertension; blood pressure; blood pressure medications; metoprolol; nebivolol; vascular oxidative stress; nitric oxide; nitric oxide synthase (eNOS); endothelium; endothelial dysfunction; endothelial cell protein expression; microvascular blood flow; flow mediated dilation; handgrip exercise; endothelial cell collection; microbubbles; Definity