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 agonistK_A(equilibrium dissociation constant) and EC₅₀values. Values ofK_Afor activation of A_2A-AdoRs byCGS21680, adenosine, and CCPA were 105, 1800, and 2630 nmol/L, respectively. In contrast, values of EC₅₀forCGS21680, 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 toCGS21680, 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.