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(Circulation. 1998;98:711-718.)
© 1998 American Heart Association, Inc.

Basic Science Reports

A_2A-Adenosine Receptor Reserve for Coronary Vasodilation

John C. Shryock, PhD; Stephen Snowdy, BS; Pier Giovanni Baraldi, PhD; Barbara Cacciari, PhD; Giampiero Spalluto, PhD; Angela Monopoli, PhD; Ennio Ongini, PhD; Stephen P. Baker, PhD; ; Luiz Belardinelli, MD

From the Departments of Medicine (J.C.S., S.S., L.B.) and Pharmacology (S.P.B., L.B.), University of Florida, Gainesville, Fla; University of Ferrara (P.G.B., B.C., G.S.), Ferrara, Italy; and Schering-Plough Research Institute (A.M., E.O.), San Raffaele Science Park, Milan, Italy.

Correspondence to Luiz Belardinelli, MD, Departments of Medicine and Pharmacology, University of Florida, PO Box 100277, Gainesville, FL 32610. E-mail ramsepd{at}medicine.ufl.edu

Background—Adenosine is a potent coronary vasodilator and causes an increase of coronary blood flow by activation of A_2A-adenosine receptors (A_2A-AdoRs). The purpose of this study was to test the hypothesis that the high potency of adenosine and adenosine analogues to cause coronary vasodilation is explained by the presence of a large A_2A-AdoR reserve ("spare receptors").

Methods and Results—A novel, irreversible antagonist of A_2A-AdoRs was used to inactivate receptors and reduce the response to agonist. Agonist-induced increases of coronary conductance before and after exposure of hearts to the irreversible antagonist were compared. Three agonists were studied: 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS21680), adenosine, and 2-chloro-N⁶-cyclopentyladenosine (CCPA). Data were analyzed to determine agonist K_A (equilibrium dissociation constant) and EC₅₀ values. Values of K_A for activation of A_2A-AdoRs by CGS21680, adenosine, and CCPA were 105, 1800, and 2630 nmol/L, respectively. In contrast, values of EC₅₀ for CGS21680, adenosine, and CCPA to increase coronary conductance were 1.5, 85, and 243 nmol/L, respectively. By use of the law of mass action, it was calculated that half-maximal responses to CGS21680, adenosine, and CCPA occurred when only 1.3%, 5%, and 9%, respectively, of A_2A-AdoRs were occupied by agonist.

Conclusions—Receptor reserves for 3 A_2A-AdoR agonists were large. The receptor reserve for A_2A-AdoRs to cause an increase of coronary conductance can explain both the high potency of adenosine to cause coronary vasodilation and the observation that an A_2A-AdoR agonist can cause coronary vasodilation without systemic effects.

Key Words: adenosine • pharmacology • receptors • circulation • vasodilation

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