A 2A -Adenosine Receptor Reserve for Coronary Vasodilation

Abstract

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 EC 50 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 EC 50 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.