Adenosine Receptors: The A_2A-Receptor Target

The Science of the A_2A-receptor

Scientists at CV Therapeutics believe that selective activation of the adenosine receptor that increases coronary blood flow – the A_2A-adenosine receptor subtype – may be useful during myocardial perfusion imaging (MPI) studies of the heart muscle to identify areas with low blood flow. A_2A-adenosine receptor activation may avoid many of the undesirable side effects associated with traditional agents administered during MPI studies.

MPI studies are usually performed in a nuclear medicine clinic. Medication is administered to the patient that temporarily increases coronary blood flow through the heart, mimicking the heart’s physical response to the increased energy demand caused by exercise. Once the equivalent of maximal exercise is reached, a small amount of radioactive substance (radionuclide) is injected into the bloodstream after blood flow through the heart increases to a level comparable to that seen in maximal exercise. The amount of radionuclide absorbed in various areas of the heart is proportional to the blood flow to the area.

An image of the area is then taken by a camera that specifically detects the distribution of radionuclide in the heart during the period of increased blood flow (vasodilation). Additional images are taken of the heart “at rest.” If the images of the heart during vasodilation and at rest show the same relative distribution of blood flow through the heart, then the test result is normal. However, if a perfusion defect is seen in the image of the vasodilated heart while the image of the heart at rest appears normal, then it is possible the defect is the result of a partial blockage caused, for example, by an atherosclerotic plaque associated with coronary artery disease, signaling the need for treatment and possibly additional testing to confirm the diagnosis. View an image series on myocardial perfusion.

MPI studies use pharmacological agents to increase coronary blood flow of the heart as if it were responding to the demands of physical exercise. Traditional agents used include dipyridamole and adenosine. Both agents act nonspecifically on the heart and are administered to patients into the vein with the aid of an infusion pump. While they are very effective at increasing coronary blood flow, their nonspecificity may also produce undesirable and uncomfortable side effects.

For example, dipyridamole is most commonly associated with chest pain, headache, and dizziness. In addition, the long half-life of dipyridamole may require lengthy patient monitoring following the procedure. Adenosine, while it has a short half-life, activates all adenosine receptor subtypes and, as a result, may cause flushing, dyspnea, and headache. The activation of other adenosine receptor subtypes may also cause sustained decreases in blood pressure (hypotension), reduced heart rate, and heart block. Adenosine is contraindicated in patients with asthma because of the risk of bronchoconstriction with the use of this agent.

In 2005, approximately 9.3 million patients underwent MPI studies. Of those, approximately 4.3 million, or more than 46%, required a pharmacologic agent to generate maximum coronary blood flow because peripheral vascular disease, arthritis, or other limiting medical conditions prevented them from completing an exercise treadmill test.

We believe that selective and specific stimulation of the adenosine receptor responsible for stressing the heart – the A_2A-adenosine receptor subtype – may potentially help avoid some of the undesirable side effects caused by the nonspecific actions of traditional agents.  Moreover, the development of an agent that could be administered into the vein without the use of an infusion pump may allow for more efficient administration during MPI studies.