Glucagon Like Peptide-1 in Remote Ischemic Conditioning
Condition: Healthy Volunteers
Study type: Interventional

Summary: 
      The study was designed to investigate whether glucagon like peptide-1 is a mediator of
      protection of endothelial function induced by remote ischemic conditioning in
      ischemia-reperfusion
    

Detailed description: 
      The mechanism behind the cardioprotective effect of remote preconditioning is incompletely
      understood. Data from experimental studies suggest that a combination of humoral and
      neurogenic factors mediate the transition of protective signals from peripheral tissues to
      the myocardium. A major break-through in the understanding of the signaling was the
      observation that vagal nerve activation is involved. Key signaling pathways in the target
      organ are likely to be mediated via the vascular endothelium which is known to play an
      important role during the early reperfusion period. Thus, animal studies have demonstrated
      that RIPC stimulates endothelial nitric oxide production secondary to down-regulation of
      arginase. It remains unclear, however, whether RIPC via activation of endothelial nitric
      oxide preserves endothelial function in humans. Additional data indicate strongly that
      glucagon-like peptide-1 (GLP-1) provides protection against ischemia-reperfusion injury in
      experimental animals models as well as in clinical studies. The role of GLP-1 in the
      protective effect of RIPC has previously not been investigated, however. The present study
      was therefore designed to determine the involvement of GLP-1 in the protection induced by
      RIPC via endothelial activation in humans. To this end we use a model of reversible
      ischemia-reperfusion injury in the forearm, and the GLP-1 antagonist exendin 9-39 (Ex 9-39).

      Objective To test the hypothesis that GLP-1 is a mediator of protection of endothelial
      function induced by RIPC in ischemia-reperfusion.

      Endpoints Primary: Change in endothelium dependent vasodilatation induced by RIPC Secondary:
      Change in plasma GLP-1

      Study subjects The study is performed on healthy volunteers 18-60 years of age. All subjects
      will undergo a screening including medical history and routine clinical examination, and
      should be free of medication. A screening blood sample includes hemoglobin, leukocyte and
      platelet count, fasting blood glucose, HbA1c, total cholesterol, LDL cholesterol, HDL
      cholesterol, triglycerides.

      Methods Endothelial function is determined in the brachial artery by flow-mediated dilation
      (FMD). Briefly, non-invasive examination of the radial artery of the non-dominant arm is
      performed with a 11 MHz (output 12 MHz) linear-array transducer connected to a Vivid E9. The
      transducer is connected to a flexible tripod to prevent movement of the probe. Images are
      recorded and saved every third second at end-diastole. Baseline radial artery diameter is
      recorded for one minute and defined as a mean from 20 images. A blood pressure cuff is placed
      around the upper part of the forearm, which is inflated to 30 mmHg above systolic pressure or
      200 mmHg for 5 min. The diameter of the radial artery is continuously recorded for 3 min
      during hyperemia following deflation of the cuff. The three frames displaying maximum
      dilatation at end-diastole (triggered from the ECG) are used to calculate a mean diameter.
      All images are analyzed with Brachial analyzer (Medical Imaging Applications, Iowa City, IA,
      USA). FMD is calculated as a percentage increase in diameter from baseline diameter according
      to the following formula: diameter following cuff deflation-baseline diameter/baseline
      diameter x 100. All evaluations are performed blinded. A decrease in endothelial function is
      an established outcome of reperfusion injury.

      Study protocol After determining the basal FMD ischemia is induced by inflating a cuff to 200
      mmHg on the upper arm for 20 min followed by reperfusion. FMD is determined again 20 min
      after the start of reperfusion . Each individual is examined on three occasions: A)
      ischemia-reperfusion without intervention, B) ischemia-reperfusion with intervention by RIPC,
      C) ischemia-reperfusion with RIPC and administration of Ex 9-39. The order of the examination
      is randomly assigned by drawing one of three numbers. RIPC is performed in cycles of 5 min of
      inflation (200 mmHg or 20 mmHg above systolic blood pressure) and 5 min deflation of an
      automatic blood pressure cuff around the left thigh. Two cycles are performed during ischemia
      and 2 cycles immediately after reperfusion. The GLP-1 receptor antagonist Ex 9-39 is
      administered as a bolus of 7500 pmol/kg followed by an iv infusion starting 15 min before the
      initial FMD and maintained until the second FMD at a rate of 500 pmol/kg/min. The dose is
      based on previous experiences from studies on humans.

      During the experimental protocols the following blood samples are collected for analysis of
      glucose, insulin, GLP-1.
    

Intervention name(s): Remote conditioning; Exendin 9-39
Intervention type(s): Other; Drug
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other