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(Circulation. 2001;104:1181.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Pharmacological Stress Myocardial Perfusion Imaging With the Potent and Selective A_2A Adenosine Receptor Agonists ATL193 and ATL146e Administered by Either Intravenous Infusion or Bolus Injection

David K. Glover, ME; Mirta Ruiz, MD; Kazuya Takehana, MD; Frank D. Petruzella, BA; Laurent M. Riou, PhD; Jayson M. Rieger, MS; Timothy L. Macdonald, PhD; Denny D. Watson, PhD; Joel Linden, PhD; George A. Beller, MD

From the Experimental Cardiology Laboratory, Cardiovascular Division, Department of Internal Medicine, University of Virginia Health System, Charlottesville.

Reprint requests to David K. Glover, ME, University of Virginia/Cardiology Division, PO Box 800500 Health Sciences System, Cobb Hall, Room 1010, Hospital Drive, Charlottesville, VA 22908-0500. E-mail dglover{at}virginia.edu

Background—— Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A_2A Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5'-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging.

Methods and Results—— In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A_2A over the A₁ and A₃ receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of ^99mTc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A_2A antagonist ZM241385 (3 µg · kg^-1 · min^-1).

Conclusions—— ATL-193 and ATL-146e are highly potent and selective Ado A_2A receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.

Key Words: adenosine • vasodilation • imaging

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