A(2A)-ADENOSINE RECEPTOR RESERVE FOR CORONARY VASODILATION

Background-Adenosine is a potent coronary vasodilator and causes an in crease of coronary blood flow by activation of A(2A)-adenosine recepto rs (A(2A)-AdoRs). The purpose of this study was to test the hypothesis that the high potency of adenosine and adenosine analogues to cause c oronary vasodilation is explained by the presence of a large A(2A)-Ado R reserve (''spare receptors''). Methods and Results-A novel, irrevers ible antagonist of A(2A)-AdoRs was used to inactivate receptors and re duce the response to agonist. Agonist-induced increases of coronary co nductance before and after exposure of hearts to the irreversible anta gonist were compared. Three agonists were studied: hyl)-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 wer e 1.5, 85, and 243 nmol/L, respectively. By use of the law of mass act ion, it was calculated that half-maximal responses to CGS21680, adenos ine, 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 hig h potency of adenosine to cause coronary vasodilation and the observat ion that an A(2A)-AdoR agonist can cause coronary vasodilation without systemic effects.