The Contribution of Endothelin to Vasomotor Function in Diseased Coronary Arteries

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.

Inclusion Criteria:

Adult men and women between the ages of 18 to 75 years will be enrolled and categorized
into one of 4 groups. The categories are defined below:

- Control patients characterized by chest pain and angiographically normal coronary
arteries.

- Chronic stable angina patients who describe a history of exertional chest pain which
is unchanged in frequency over the preceding month, and who have at least a 70%
stenosis in a coronary artery.

- Unstable angina patients who describe chest pain at rest or with minimal exertion
over the preceding 2 weeks, and who have an identifiable culprit stenosis in a
coronary artery.

- Cardiac transplant recipients who are undergoing routine annual surveillance cardiac
catheterization.

Exclusion Criteria:

Patients with the following will be excluded from the study:

- Angiographic exclusion criteria: *Left main coronary artery disease or severe triple
vessel disease; *Unstable angina without any identifiable culprit lesion.

- Severe left ventricular dysfunction (ejection fraction < 40%) or clinical cardiac
failure.

- Nitroglycerin required in the preceding 4 hours prior to the investigation.

- Severe renal, hepatic or hematologic abnormalities.

- Inability to obtain written informed consent.