Model System for Transient Forearm Blood Vessel Dysfunction
Condition: Limb Ischemia; Ischemic Preconditioning
MeSH terms: Ischemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will develop a model system that can be used to test medications for improving the
      ability of blood vessels to resist damage from diseases such as heart attack and stroke. The
      endothelium (inner layer of blood vessels) has built-in defense mechanisms to prevent
      blockage of blood flow, including the ability to stretch the vessel when it senses that blood
      flow is threatened. People with heart attack risk factors, such as high cholesterol, smoking
      and diabetes lose this ability. This study will develop a model that can measure the response
      to a lack of blood flow in the arm and be used to test new medicines to improve blood vessel
      health.

      Healthy males between 18 and 45 years of age who have no history of high blood pressure, high
      cholesterol, or diabetes and who have not smoked for at least 3 months before entering the
      study may be eligible to enroll.

      Participants lie in an adjustable reclining bed. Small catheters (tubes) are placed in the
      artery and vein of the forearm of the non-dominant arm at the inside of the elbow. Blood
      samples are collected from the tubes. Then, pressure cuffs are placed on both wrists and
      upper arms. A strain gauge (rubber band-type device) is placed around the forearms. The
      pressure cuffs are inflated and blood flows into the forearm, stretching the strain gauge at
      a rate proportional to the blood flow. Then, small doses of acetylcholine (a medicine that
      causes blood vessels to expand) are injected into the artery tube. After 20 minutes, blood
      flow to the non-dominant arm is blocked by inflating the pressure cuff. The subject squeezes
      a rubber ball about every 2 seconds for 90 seconds. The cuff is deflated after 15 minutes and
      blood samples are withdrawn from the tube in the vein. After 15 minutes, the procedure is
      repeated one more time.
    

Detailed description: 
      Endothelial dysfunction denotes abnormal contractile function of the inner lining of blood
      vessels. Endothelial dysfunction is associated with hypertension, hypercholesterolemia,
      atherosclerosis and diabetes and is an independent risk factor for cardiovascular disease. In
      normal physiology, endothelial cells synthesize and release factors that modulate blood
      vessel growth, inflammation, homeostasis, and vascular tone. Recently, endothelial
      dysfunction has been recognized as an early event in ischemia-reperfusion (IR) injury. IR
      injury causes damage to tissue and is important in many settings including acute coronary
      artery occlusions and cerebral ischemia. A model to examine the physiology of IR induced
      endothelial dysfunction and to test pharmacologic agents to prevent IR induced endothelial
      dysfunction is of paramount importance given the rise in cardiovascular and cerebrovascular
      disease. Recently in Protocol 06-H-0024, our group found that 20 minutes of ischemic stress
      causes no absolute endothelial dysfunction to the forearm using venous plethysmography to
      measure blood flow, despite numerous publications that support this model. We believe that
      the previously published data are based on a computational error resulting in an erroneous
      data interpretation (discussed in the introductory section of this proposal). Using NMR
      spectroscopy in protocol 06-H-0024 we have found that by adding exercise to exhaustion
      (usually 1 to 2 minutes of concentric exercise) to a 15-minute period of forearm ischemia
      results in a significantly more robust metabolic stress to the forearm, than 20 minutes of
      ischemia alone. Given the potential utilization of the restoration of endothelial function as
      a therapeutic strategy, we propose this pilot study to examine whether 15 minutes of ischemia
      with exercise to exhaustion (usually 1-2 minutes of concentric exercise) will cause transient
      IR dependent blunting of endothelial vasodilation as measured by venous plethysmography. In
      this study, an extension of Protocol 06-H-0024, we hypothesize that in human subjects the
      addition of concentric exercise to exhaustion, as a means to deplete high energy phosphate
      stores, will contribute to the development of transient endothelial dysfunction when
      performed in parallel with a 15-minute forearm ischemic stress. The establishment of a human
      system to enable the study of transient forearm vessel endothelial dysfunction will enable us
      to explore therapeutic interventions to protect against endothelial dysfunction.
    

Intervention name(s): Limb Ischemia; Acetylcholine
Intervention type(s): Procedure; Drug
Intervention MeSH terms: Acetylcholine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Forearm Ischemia; Endothelial Function; Acetyicholine Vasodilation; Venous Plethysmography; Healthy Volunteer; HV