The Contribution of Endothelin to Vasomotor Function in Diseased Coronary Arteries
Condition: Atherosclerosis, Coronary
MeSH terms: Atherosclerosis; Coronary Artery Disease; Myocardial Ischemia
Study type: Interventional

Summary: 
      The purpose of the study is to assess the importance of a substance called endothelin.
      Endothelin is produced by coronary arteries. This study examines this substance to determine
      whether it has an effect on controlling blood flow in coronary arteries. When these arteries
      release too much endothelin, the blood flow to the heart muscle is reduced and this may be
      important in heart conditions. This protocol examines an investigational drug called BQ-123
      to see if it blocks the effect of endothelin. We assess the blood flow in the coronaries and
      evaluate the effects of BQ-123. It is anticipated that this endothelin blocker will open up
      coronary arteries and increase the blood flow to the heart.
    

Detailed description: 
      There are many substances that influence the diameter of the coronary artery and a number of
      these are actually released by the lining of the coronary arteries (referred to as the
      endothelium). Over the past 15 years, our laboratory has been instrumental in establishing
      the role of endothelium-released relaxing factors which relax (open) the coronary arteries.
      We are now focussing our attention on factors which constrict the coronary artery, in
      particular a substance called endothelin-1 (ET-1). This potent constrictor substance has been
      found to accumulate at coronary artery sites which may produce unstable angina (ie the
      culprit lesion or stenosis). Hence ET-1 may produce localized constriction of a coronary
      stenosis thereby further narrowing the remaining lumen and cutting off blood flow to the
      heart muscle and thus leading to unstable angina.

      If ET-1 is important in the development of unstable angina, then medications which inhibit
      the effects of ET-1 should improve the condition. To achieve a blockade of ET-1, inhibitors
      of the two receptors (ET-A and ET-B) responsible for ET-1's action must be administered.
      Animal and human studies have demonstrated that a blockade of the ET-A receptor by the new
      antagonist, BQ-123, inhibits most of the ET-1 induced constrictor response. BQ-123 has been
      safely administered systemically by intravenous infusion and locally in the human forearm
      where it produces dilation of the forearm arteries. It has not been previously administered
      into human coronary arteries.

      Consented patients whose routine diagnostic angiogram shows suitable anatomy (i.e., normal
      angiogram for the control group, or one/two vessel coronary artery disease with an
      identifiable culprit stenosis) will have placement of a coronary artery angiographic
      catheter. Placement of this catheter does not require an additional puncture of an artery
      (already performed in the routine diagnostic angiogram).

      The angiographic catheter allows visualization of the internal diameter of the coronary
      arteries by the injection of a radiographic contrast with the image being recorded on a cine
      film. Specialized imaging machines will measure the diameter of the vessel.

      Through the angiographic catheter, an infusion catheter (by which the drugs can be
      administered) and a coronary Doppler flow wire are placed in the coronary artery. The latter
      instrument is a well-established tool for measuring coronary blood flow.

      After establishing baseline values for heart rate, blood pressure, culprit stenosis internal
      diameter and coronary blood flow, the following sequential intracoronary infusions will be
      undertaken:

        1. Infusion of the endothelin antagonist, BQ-123, over a 60 minute period. This inhibitor
           requires up to 60 minutes exerting a full effect;

        2. Adenosine bolus injection, to assess the vasodilation capacity of the small coronary
           arteries; and

        3. Nitroglycerin bolus injection, to assess the maximal vasodilation capacity of the large
           coronary arteries.

      At 5, 15, 30, 45, and 60 minutes of endothelin antagonist infusion, and immediately after the
      bolus injections, the above parameters will be reassessed. It is anticipated that this
      research protocol will be completed within 90 minutes.

      Following the research protocol, the patient will undergo appropriate coronary intervention
      as dictated by the clinical situation. If coronary atherectomy is required for clinical
      indications, then the specimen extracted by this procedure will be sent for specific analysis
      of endothelin-1 content. A correlation between the amount of endothelin at the culprit
      stenosis and the response to the endothelin antagonist can then be examined. In cardiac
      transplant recipients, endomyocardial biopsies are also routinely obtained for clinical
      purposes at the time of catheterization. One of these specimens will be used for ET-1
      immunoreactivity analysis. A total of 2 teaspoons of blood will be taken and frozen for
      analysis.
    

Intervention name(s): Drug Infusion (BQ-123)
Intervention type(s): Drug
Intervention MeSH terms: cyclo(Trp-Asp-Pro-Val-Leu)
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)