A2A-adenosine receptor reserve for coronary vasodilation

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-N-6-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.