Effects of Nebivolol on Microvascular Perfusion in the Skeletal Muscles During Exercise in Hypertensive Patients
In 32 untreated hypertensive subjects, we will measure BP; 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 Octafluoropropane microbubble contrast agents (Definity) in untreated stage 1 hypertensive subjects. To obtain FMD, 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 subjects 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 immuno-fluorescent technique. To assess the microvascular perfusion in the skeletal muscle, Definity (IND # 104,397) will be administered at the rate of 0.20 to 0.27 ml/min, at baseline and after 5 minutes of rhythmic hand grip exercise at 30% of maximal voluntary contraction. Administration of microbubble contrast agents during ultrasonography have been shown to be more reliable than the traditional Doppler ultrasonography and other noninvasive technique in assessing skeletal muscle perfusion in humans(14,15). The total dose of Definity use will not exceed 2 vials per study subject per day or visit. Then, we will 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 [AND]amp;gt; 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 (Nevibilol or Metoprolol). Then, we 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 same subjects.
(1). Patients with stage 1 primary untreated hypertension (BP between 140-159/90-99 mmHg), age 18-65, without target organ disease.